JP2006518333A - Heteroarylalkanoic acids as integrin receptor antagonists - Google Patents

Abstract

The present invention provides compounds or pharmaceutical compositions comprising a pharmaceutically acceptable salt of Formula I, and methods of selectively inhibiting or antagonizing the Arufabuibeta ₃ and / or Arufabuibeta ₅ integrin without significantly suppressed Arufabuibeta ₆ integrin .

Description

The present invention provides a Arufabuibeta ₃ and / or pharmaceutical is Arufabuibeta ₅ integrin antagonist (compound), these antagonists themselves are useful as pharmaceutical compositions, as well as the state of Arufabuibeta ₃ and / or Arufabuibeta ₅ integrins are involved It relates to said medicament (compound) useful in a method of treatment.

Integrin αvβ ₃ (also known as vitronectin receptor) is a member of the integrin family of heterodimeric transmembrane glycoprotein complexes and is involved in cell adhesion and signal transduction processes. Integrin Arufabuibeta ₃ is expressed on many types of cells, adhesion of osteoclasts to the bone matrix, including migration and angiogenesis of vascular smooth muscle cells, in several biologically relevant processes Has been acknowledged to be involved.

Integrin Arufabuibeta ₃ is tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, osteopenia, angiogenesis including tumor angiogenesis, retinopathy including macular degeneration Has been shown to affect a variety of conditions or diseases including arthritis, arthritis such as rheumatoid arthritis, periodontal disease, psoriasis, and smooth muscle cell migration (eg, restenosis atherosclerosis) . Series of compounds of the present invention is a Arufabuibeta ₃ antagonists can them alone or in combination with other therapeutic agents, for use in the treatment or modulation of various conditions or diseases above. In addition, it has also been found that such agents would be useful as antiviral, antifungal and antimicrobial agents.

Integrin αvβ ₅ has an influence on the new blood vessel formation. Accordingly, the compounds of the present invention to act as antagonists of Arufabuibeta ₅ integrin suppresses neovascularization, angiogenesis metastasis, tumor growth, probably effective in the treatment and prevention of macular degeneration and diabetic retinopathy.

antagonist or dual αvβ _{3 /} αvβ ₅ antagonist Arufabuibeta ₃ is treatment or prevention of other bone diseases such as osteopenia or osteoporosis or Paget's disease or humoral hypercalcemia of malignancy; atherosclerosis after vascular treatment Treatment or prevention of neointimal thickening that can cause infectious disease or restenosis; Treatment or prevention of periodontal disease; Treatment and prevention of viral infection or other pathogens; Treatment of neoplasms; Tumor metastasis, diabetic retinopathy, It can be a useful therapeutic agent for treating many pathological conditions, including the treatment of pathological angiogenesis or neovascularization such as macular degeneration, rheumatoid arthritis or osteoarthritis.

Compounds that antagonize Arufabuibeta ₅ and / or Arufabuibeta ₃ receptors have been described in the literature. For example, WO 01/96334 provides a useful heteroaryl alkanoic acid compounds as Arufabuibeta ₃ and / or Arufabuibeta ₅ Inbibita.

Summary of the Invention
As demonstrated from ongoing research on integrin antagonists and the shortcomings of compounds and methods in the art, it has fewer side effects than previously described compounds and has improved efficacy in oral bioavailability and sustained action, etc. shows the pharmacodynamic and pharmacokinetic properties, are low molecular and non-peptide selective Arufabuibeta ₃ and / or Arufabuibeta ₅ antagonist is still required. Such compounds bind to Arufabuibeta ₃ and / or Arufabuibeta ₅ receptors and is involved in cell adhesion and activation, the treatment of various diseases listed above, it Eyo become effective in the prevention or suppression.

The compounds of the present invention, 1) Arufabuibeta ₃ integrin antagonists; or 2) αvβ ₅ integrin antagonists or 3) mixed or dual αvβ ₃ / αvβ ₅ antagonists. The present invention includes compounds that inhibit each integrin and also includes pharmaceutical compositions containing such compounds. The present invention further provides a method for treating or preventing a condition Arufabuibeta ₃ and / or Arufabuibeta ₅ receptors are involved, the pharmaceutical compounds and the invention of the present invention to a mammal in need of such treatment There is provided a method as described above comprising administering a therapeutically effective amount of the composition. Administration of such compounds and compositions of the present invention may include angiogenesis, tumor metastasis, tumor growth, skeletal malignancy of breast cancer, osteoporosis, Paget's disease, malignant humoral hypercalcemia, retinopathy, macular degeneration, Suppresses arthritis such as rheumatoid arthritis, periodontal disease, restenosis and smooth muscle migration including atherosclerosis, and microbial or viral diseases.

The compounds of the present invention can be used alone or in combination with other therapeutic agents and used to treat or modulate the various conditions or diseases described above.
To prevent side effects of hemorrhagic associated with alpha _IIb beta ₃ of suppression, the high selectivity of Arufabuibeta ₃ and Arufabuibeta ₅ for alpha _IIb beta ₃ may be effective.

  The present invention provides the following formula (I):

A group of compounds represented by: or a pharmaceutically acceptable salt thereof, wherein ring A:

Is a 4-8 membered monocyclic or 7-12 membered bicyclic ring containing 1-5 heteroatoms selected from the group consisting of O, N or S; saturated or unsaturated Alkyl, haloalkyl, aryl, heteroaryl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide, acyl, acylamino, alkylsulfone , Sulfonamide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, carboxyamide, cyano, and — (CH ₂ ) _m COR (where m is 0-2, R is hydroxy, alkoxy, alkyl Or is amino) Optionally substituted with one or more substituents; provided that when Y ^{4 in} formula (I) is H, ring A is:

As shown in the above, the XY containing the side chain may not be a monocyclic oxazole linked by carbon at the 2-position, and the ring A further contains a carboxylamide, sulfone, sulfonamide or acyl group. Also good.

A ¹ has the following formula:

5 to 9-membered monocyclic or 8 to 14-membered polycyclic heterocycle containing at least one nitrogen atom and selected from O, N, S, SO ₂ or CO May contain heteroatoms or groups; may be saturated or unsaturated; hydroxy, alkyl, alkoxy, alkoxyalkyl, thioalkyl, haloalkyl, cyano, amino, alkylamino, halogen, acylamino, sulfonamide and —COR (wherein, R represents hydroxy, alkoxy, alkyl or amino) may be substituted with one or more R ^K is selected from the group consisting of;
Or A ¹ is represented by the following formula:

Wherein Y ¹ is selected from the group consisting of N—R ² , O and S;
R ² is H; alkyl; aryl; hydroxy; alkoxy; cyano; amide; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; Selected from the group consisting of:
R ² together with R ⁷ is a 4-12 membered heterocycle containing two nitrogens (from lower alkyl, thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxy ester Optionally substituted with one or more selected substituents;
Or R ² together with R ⁷ forms a 4-12 membered heterocycle (which may be unsaturated) containing one or more heteroatoms selected from O, N and S;
Or R ² together with R ⁷ forms a 5-membered heteroaromatic ring fused to one aryl or heteroaryl ring;
R ⁷ (when not together with R ² ) and R ⁸ are independently H; alkyl; aralkyl; amino; alkylamino; hydroxy; alkoxy; arylamino; amide; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; Arylthiocarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl; cycloalkyl; bicycloalkyl; aryl; acyl;
Or NR ⁷ and R ⁸ together are 4 to 12 membered monocyclic or bicyclic ring containing one nitrogen (where the ring is one or more selected from lower alkyl, carboxyl derivatives, aryl or hydroxy) And may contain one heteroatom selected from the group consisting of O, N and S);
R ⁵ is selected from the group consisting of H and alkyl]
Or A ¹ is represented by the following formula:

Wherein Y ² is selected from the group consisting of alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycle;
Z ₁ is selected from the group consisting of CH ₂ , CH ₂ O, O, NH, CO, S, SO, CH (OH) and SO ₂ ;
Z ₂ is a C 1-5 linker that may contain one or more heteroatoms selected from the group consisting of O, S and N;
Z ₁ -Z ₂ may further comprise a carboxyamide, sulfone, sulfonamide, alkenyl, alkynyl or acyl group;
(Wherein the carbon and nitrogen atoms of the Z ₁ -Z ₂ is alkyl, alkoxy, thioalkyl, alkyl sulfonate, aryl, alkoxyalkyl, hydroxyalkyl, alkylamino, heteroaryl, Arikeniru, alkynyl, carboxyalkyl, halogen, haloalkyl or acylamino May be substituted);
Z ₁ -Z ₂ is a 5-membered or 6-membered aryl or heteroaryl ring optionally substituted with R ^c (wherein the heteroaryl ring is selected from O, N and S 1 to 3 R ^c is composed of H, alkyl, haloalkyl, aryl, heteroaryl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, alkoxy, carboxyamide, or cyano. Selected from the group].

X is a group consisting of —CHR ^e —, —NR ^f —, —O—, —S—, —SO ² — and —CO— (where R ^e is H, lower alkyl, alkoxy, cycloalkyl, Alkoxyalkyl, hydroxy, alkynyl, alkenyl, haloalkyl, thioalkyl or aryl; when R ^e is hydroxy, this hydroxy group can also be combined with the carboxylic acid functionality of the chain to form a lactone; R ^f Is selected from the group consisting of H, alkyl, aryl, aralkyl and haloalkyl);
Y is a group consisting of (CH ₂ ) _p , —CHR ^g —, —NR ^g —, CO and SO ² , where R ^g is H, alkyl, haloalkyl, alkoxyalkyl, alkynyl, aryl, heteroaryl, Selected from the group consisting of aralkyl, hydroxy, alkoxy and carboxyalkyl; p is 0 or 1.

The XY group may comprise a moiety selected from acyl, alkyl, sulfonyl, amino, ether, thioether, carboxamide, sulfonamido, aminosulfonyl, and olefins;
Y ³ and Y ⁴ are independently selected from the group consisting of H, alkyl, haloalkyl, halogen, aryl, aralkyl, heteroaralkyl, heteroaryl, hydroxyalkyl, alkenes and alkynes, wherein the alkyl chain is linear Or it may be branched, may contain one or more heteroatoms selected from the group consisting of N, O and S, and in addition, sulfone, sulfonamide, nitrile, carboxyamide, carboalkoxy Or may contain a carboxyl group; the aryl and heteroaryl rings can be monocyclic or bicyclic optionally containing 1 to 5 heteroatoms, and said rings are saturated Or unsaturated, as well as such rings can be alkyl, haloalkyl, aryl. , Heteroaryl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide, acyl, acrylicamino, alkylsulfone, sulfonamide, allyl, alkenyl , Methylenedioxy, ethylenedioxy, alkynyl, carboxamide, cyano, and — (CH ₂ ) _m COR (where m is 0-2 and R is hydroxy, alkoxy, alkyl, or amino) ^May be substituted with one or more substituents selected from the group consisting of: provided that when Y ³ or Y ⁴ is H, Y ⁵ may be C or N, and Y ⁵ may be C Is;
Or Y ³ together with Y ⁴ is a 3-8 membered monocyclic or 7-11 membered bicyclic ring, B:

And ring B may contain one or more double bonds and contain one or more heteroatoms or functional groups selected from O, NR ^g , S, CO or SO ₂ Optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, halogen, haloalkyl, alkoxy, alkyne, cyano, alkylsulfone, sulfonamido, carboalkoxy and carboxyalkyl;
Or, X together with Y ³ is a 3-7 membered monocyclic C:

And ring C may contain one or more double bonds and contain one or more heterocycles or functional groups selected from O, NR ^g , S, CO or SO ² Optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, alkoxy, haloalkyl, hydroxyalkyl or alkoxyalkyl; and R ^b is X ₂ -R ^h [where , X ₂ is selected from the group consisting of O, S and NR ^j (R ^h and R ^j are independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl and alkoxyalkyl)] It is.

The compounds of the present invention include various integrin antagonists of novel heteroarylalkanoic acids.
The present invention includes the following compounds:
3- (3,5-ditert-butylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid (trifluoroacetate);
3- (3-tert-butyl-5-iodophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid;
3- (3-tert-butyl-5-bromophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid;
3- (5-tert-butyl-2-hydroxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid;
3- [3,5-ditert-butyl-2- (carboxymethoxy) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (5-tert-butyl-2-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid;
3- (3,5-ditert-butyl-4-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl]- 1,2,4-oxadiazol-5-yl} butanoic acid;
3- {3-tert-butyl-5- [2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl] -phenyl} -4- {3- [3- (5,6 , 7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3,4-Dichlorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 trifluoroacetic acid -Oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- (3-fluoro-4-methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid;
3- (4-Phenoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid;
3- (1-Benzofuran-2-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetate , 4-oxadiazol-5-yl} butanoic acid;
3- [4- (Benzyloxy) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetic acid , 4-oxadiazol-5-yl} butanoic acid;
3- [4- (Methylsulfonyl) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetic acid , 4-oxadiazol-5-yl} butanoic acid;
Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3- [4- (trifluoromethoxy) phenyl] butanoic acid;
3- (3-Furyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxatriacetate Diazol-5-yl} butanoic acid;
Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3-thien-3-ylbutanoic acid;
Hydrochloric acid 3- (2,3-dihydro-1,4-benzodioxin-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl ) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} -3- [3- (trifluoromethoxy) phenyl] butanoic acid;
Hydrochloric acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} -3- (3,4,5-trifluorophenyl) butanoic acid;
Hydrochloric acid 3- (2,2-difluoro-1,3-benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- [3-fluoro-5- (trifluoromethyl) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl]- 1,2,4-oxadiazol-5-yl} butanoic acid;
3- (6-methoxy-2-naphthyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 hydrochloride -Oxadiazol-5-yl} butanoic acid;
3- (6-Methoxypyridin-3-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 -Oxadiazol-5-yl} butanoic acid;
3- (4-Cyanophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid;
3- (3-Cyanophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid;
3-Benzyl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole-5 trifluoroacetate -Yl} butanoic acid;
3- (4-Fluoro-3-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, trifluoroacetic acid, 2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- (3-fluoro-5-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid;
3- (2-Methyl-1,3-benzothiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl hydrochloride ] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3-[(2- (4-methoxyphenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine- 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (2-Methyl-1,3-benzothiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl hydrochloride ] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- [2- (3,5-Difluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine hydrochloride -2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- [2- (3,4-Difluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine hydrochloride -2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- [2- (2-furyl) 1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl ) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3,4-Dimethoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid;
3- (3,5-dimethoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid;
3- (3,5-dichlorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 trifluoroacetic acid -Oxadiazol-5-yl} butanoic acid;
3- (3,5-Difluorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid;
3- (3-Fluoro-4-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetic acid , 4-oxadiazol-5-yl} butanoic acid;
Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3- [4- (trifluoromethyl) phenyl] butanoic acid;
3- (2-Methyl-1,3-thiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) trifluoroacetate Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1-Phenyl-1H-pyrazol-4-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] trifluoroacetate -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1-Benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 hydrochloride -Oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- (2,3-dihydro-1-benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (3- {3-[(pyridin-2-ylamino) methyl] phenyl} -1,2,4-oxadiazole-5 hydrochloride -Yl) butanoic acid;
3- (7-Fluoro-1,3-benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2) trifluoroacetic acid -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1,3-Benzoxazol-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1 hydrochloride , 2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Methyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-trifluoroacetic acid 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Ethyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-trifluoroacetic acid 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Phenyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-trifluoroacetic acid 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
Trifluoroacetic acid [1-benzoyl-4-({3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} methyl) piperidin-4-yl] acetic acid;
Trifluoroacetic acid [1-benzoyl-4-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) piperidin-4-yl] acetic acid ;
Trifluoroacetic acid [1- (tert-butoxycarbonyl-4-({3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 -Oxadiazol-5-yl} methyl) piperidin-4-yl) acetic acid;
Trifluoroacetic acid [1- (tert-butoxycarbonyl) -4-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) piperidine- 4-yl] acetic acid;
3- (4-Methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid;
3- (3-Chlorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole hydrochloride -5-yl} butanoic acid;
Hydrochloric acid 3- (4-methoxy-3-methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid;
3- [4- (Methylthio) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid;
3- (1-Methyl-1H-indol-3-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] trifluoroacetate -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1,1′-biphenyl-4-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, 2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Bromophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid;
3- (4-Bromophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid;
3- (3-phenoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3-[(3- (benzyloxy) phenyl)]-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid;
3- (3-Bromo-4-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, trifluoroacetic acid, 2,4-oxadiazol-5-yl} butanoic acid;
Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3- (3,4,5-trimethoxyphenyl) butanoic acid;
3- (2-Naphtyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole hydrochloride -5-yl} butanoic acid;
3- (3-Nitrophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid;
3- (3-Methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid;
3- (2-Furyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole hydrochloride -5-yl} butanoic acid;
3- (2-Methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid, TFA;
4- {3- [3- (3,4-Dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) propyl] -1,2,4-oxadiazole-5 -Yl} -3- (3,5-dimethoxyphenyl) butanoic acid, TFA;
3-Benzo [1,3] dioxol-5-yl-4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene-2- Yl) -propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3- (3-Fluoro-4-methoxyphenyl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl ) -Propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3- (3,5-difluorophenyl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl)- Propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3- (3,5-Dimethoxyphenyl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl)- Propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3- (2-Methylbenzothiazol-5-yl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene-2- Yl) -propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (1,2,3,5-tetrahydropyrido [2,3-e] [1,4] oxazepine -8-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid, TFA;
3- (3,5-Dimethoxyphenyl) -4- {3- [3- (1,2,3,5-tetrahydropyrido [2,3-e] [1,4] oxazepin-8-yl) propyl ] -1,2,4-oxadiazol-5-yl} butanoic acid, TFA;
Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] propyl} -1,2,4-oxadi Azol-5-yl) butanoic acid;
3- (3-Fluorophenyl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] propyl} -1,2,4-oxadiazol-5-yl) trifluoroacetate Butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (3- {3- [6- (ethylamino) pyridin-2-yl] propyl} -1,2,4-trifluoroacetic acid Oxadiazol-5-yl) butanoic acid;
3- (3-Fluorophenyl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] propyl-1,2,4-oxadiazol-5-yl) butane trifluoroacetate acid;
3- (1,3-Benzodioxol-5-yl) -4- (3- {4-[(4-methylpyridin-2-yl) amino] butyl} -1,2,4-oxadiazole -5-yl) butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (3- {4-[(6-methylpyridin-2-yl) amino] butyl} -1,2,4-oxadiazole -5-yl) butanoic acid;
(2, {6- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] pyridin-3-yl} cyclopropyl) acetic acid;
3-methyl-4- {6- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] pyridin-3-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl trifluoroacetate ] -1,3,4-oxadiazol-2-yl} butanoic acid;
3- (3-Fluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3,4-trifluoroacetic acid Oxadiazol-2-yl} butanoic acid;
3- (3-Fluoro-4-methoxyphenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, trifluoroacetic acid, 3,4-oxadiazol-2-yl} butanoic acid;
3- (3,5-Dimethoxyphenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3, trifluoroacetic acid 4-oxadiazol-2-yl} butanoic acid;
3- (2-Methyl-1,3-thiazol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) trifluoroacetic acid Propyl] -1,3,4-oxadiazol-2-yl} butanoic acid;
3- (4-Fluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3,4-trifluoroacetic acid Oxadiazol-2-yl} butanoic acid;
3- (3,5-Difluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3, trifluoroacetic acid 4-oxadiazol-2-yl} butanoic acid;
3- (3,5-Difluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3, trifluoroacetic acid 4-thiadiazol-2-yl} butanoic acid;
3- (4-Fluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3,4-trifluoroacetic acid Thiadiazol-2-yl} butanoic acid;
3- (2-Methyl-1,3-thiazol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) trifluoroacetic acid Propyl] -1,3,4-thiadiazol-2-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl trifluoroacetate ] -1,3,4-thiadiazol-2-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] isoxazole- 5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -2H -Tetraazol-2-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1H -Tetraazol-1-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] -1H -Pyrazol-5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] isoxazol-5-yl} butanoic acid ;
3- [2- (4-Chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ) Ethoxy] isoxazol-5-yl} butanoic acid;
3 -Benzo [1,3] dioxol-5-yl-4- {3- [2- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl ) -Ethoxy] -isoxazol-5-yl} butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {3-oxo-2- [2- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohept Ten-2-yl) -ethyl] -2,3-dihydro-isoxazol-5-yl} butyric acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6 -Yl) ethoxy] isoxazol-5-yl} butanoic acid, TFA;
3- (1,3-Benzodioxol-5-yl) -4- {2- [2- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6 -Yl) ethyl] -3-oxo-2,3-dihydroisoxazol-5-yl} butanoic acid, TFA;
3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (1,2,3,5-tetrahydropyrido [2,3-e] [1,4] oxazepine -8-yl) ethoxy] isoxazol-5-yl} butanoic acid, TFA;
3- (1,3-Benzodioxol-5-yl) -4- {3-oxo-2- [2- [1,2,3,5-tetrahydropyrido [2,3-e] [1 , 4] Oxazepine-8-yl] ethyl] -2,3-dihydroisoxazol-5-yl} butanoic acid, TFA;
3- (1,3-Benzodioxol-5-yl) -4- (3- {2- [5- (methoxymethyl) -6- (methylamino) pyridin-2-yl] ethoxy} isoxazole-5 -Yl) butanoic acid, TFA;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (5,5-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine- 6-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (2-Methyl-1,3-benzothiazol-5-yl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] Pyrazin-6-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Fluoro-4-methoxyphenyl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (6-Methoxypyridin-3-yl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1,3-benzodioxol-5-yl) -4- (3- {2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl] thio} -1H-1,2,4-triazol-5-yl) butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (1-methyl-5-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ) Ethyl] thio} -1H-1,2,4-triazol-3-yl) butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (4-methyl-5-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ) Ethyl] thio} -4H-1,2,4-triazol-3-yl) butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine- 6-yl) ethoxy] isoxazol-5-yl} butanoic acid;
3- (1,3-benzodioxol-5-yl) -4- (3- {2- [6- (methylamino) pyridin-2-yl] ethoxy} isoxazol-5-yl) butanoic acid; and
3- (6-Methoxypyridin-3-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] isoxazol-5-yl} Relates to butanoic acid.

In another embodiment, the present invention provides the following compound:
3-methyl-4- (3- {3-pyridin-2-ylamino) methyl] phenyl} -1,2,4-oxadiazol-5-yl) butanoic acid;
3-methyl-4- (3- {4-[(pyridin-2-ylamino) methyl] phenyl} -1,2,4-oxadiazol-5-yl) butanoic acid;
3,3-dimethyl-4- {4- [4- (pyridin-2-ylamino) butyl] -1,3-thiazol-2-yl) butanoic acid;
[1-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) cyclo-pentyl] acetic acid;
4-phenyl-4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} -butanoic acid;
2-phenyl-4- {3- (4-pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl) butanoic acid;
3,3-Dimethyl-4- {3- [2- (2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) ethyl] -1,2,4-oxadi Azol-5-yl} butanoic acid;
[1-({3- [2- (2-Methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) ethyl] -1,2,4-oxadiazole-5- Yl} methyl) cyclopentyl] acetic acid;
4- {3- [2- (2-Methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) ethyl] -1,2,4-oxadiazol-5-yl} -4-phenylbutanoic acid;
4- {3- [2- (2-Methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) ethyl] -1,2,4-oxadiazol-5-yl} -2-phenylbutanoic acid;
4- {3- [2- (2-Methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) ethyl] -1,2,4-oxadiazol-5-yl} -2-phenylbutanoic acid;
3,3-Dimethyl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole-5 Il} butanoic acid;
[1-({3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} methyl) Cyclopentyl] acetic acid;
4-Phenyl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} Butanoic acid;
2-Phenyl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} Butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1 , 2,4-oxadiazol-5-yl} butanoic acid;
3, (1,3-Benzodioxol-5-yl) -4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butane acid;
3-quinolin-3-yl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole- 5-yl} butanoic acid;
3-quinolin-3-yl-4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid;
3- (3-methoxyphenyl) -4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (4-Methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid;
3- (4-methoxyphenyl) -4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Fluorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid;
3- (3-fluorophenyl) -4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (4-Fluorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid;
3- (4-fluorophenyl) -4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} -3- [ 3- (trifluoromethyl) phenyl] butanoic acid;
4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} -3- [3- (trifluoro-methyl) -phenyl] butanoic acid;
3- (3-Hydroxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid;
3- (3-hydroxyphenyl) -4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3-Pyridin-3-yl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole- 5-yl} butanoic acid;
3-pyridin-3-yl-4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3-phenyl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} Butanoic acid;
3-phenyl-4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3-methyl-3-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} -methyl) pentanoic acid;
[1-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) -cyclohexyl] acetic acid;
3-methyl-3-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} -methyl) -hexanoic acid;
3,4-dimethyl-3-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) -pentanoic acid;
3-ethyl-3-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) -pentanoic acid;
4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3-methyl-3-phenyl-4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3-Methyl-3- {3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -propyl]-[1,2,4] oxadiazole- 5-ylmethyl} -pentanoic acid;
3-Methyl-3- {3- [3- (5,6,7,8-tetrahydro- [1,8] -naphthyridin-2-yl) -propyl]-[1,2,4] oxadiazole- 5-ylmethyl} -hexanoic acid;
3,4-Dimethyl-3- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] -oxadi Azol-5-ylmethyl} -pentanoic acid;
3-ethyl-3- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] -oxadiazole- 5-ylmethyl} -pentanoic acid;
3-Methyl-3-phenyl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] oxa Diazol-5-yl} -butyric acid;
3-Phenyl-3- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] oxadiazole-5 -Ylmethyl} -pentanoic acid;
3-Phenyl-3- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] oxadiazole-5 -Ylmethyl} -hexanoic acid;
4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] oxa-diazol-5-yl}- Butyric acid;
3-Methyl-3-pyridin-3-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2 , 4] oxadiazol-5-yl} -butyric acid;
(1-acetyl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] oxadiazole- 5-ylmethyl} -piperidin-4-yl) -acetic acid;
(1- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) propyl]-[1,2,4] oxadiazol-5-ylmethyl}- (Cyclohexyl) -acetic acid;
3-methyl-3-pyridin-3-yl-4- {3- [4- (pyridin-2-ylamino) butyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
4- (benzyloxy) -3-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) -butanoic acid;
4- [4- (N-pyridin-2-yl-beta-alanyl) piperazin-1-yl] butanoic acid;
4- {4- [3- (pyridin-2-ylamino) propyl] piperazin-1-yl} butanoic acid;
2-methyl-6- [3- (2-pyridylamino) propoxy) -3-pyridinebutanoic acid;
β, β-dimethyl-3- [5- (2-pyridinylamino) pentyl] -1,2,4-oxadiazole-5-butanoic acid;
β, β-dimethyl-3- [4- (2-pyridinylamino) butyl] -1,2,4-oxadiazole-5-butanoic acid;
β, β-dimethyl-3-[[[2- (2-pyridylamino) ethyl] thio] methyl] -1,2,4-oxadiazole-5-butanoic acid;
4-carboxymethyl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] oxadiazole- 5-ylmethyl} -piperidine-1-carboxylic acid tert-butyl ester;
(1-Benzol-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] oxadiazole- 5-ylmethyl} -piperidin-4-yl) -acetic acid;
[4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) propyl]-[1,2,4] oxadiazol-5-ylmethyl}- 1- (2,2,2-trifluoroacetyl) -piperidin-4-yl] -acetic acid;
4- (phenylthio) -3-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) butanoic acid;
4- (Phenylthio) -3-({3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole-5 -Yl} methyl) butanoic acid;
3-methyl-4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid hydrochloride;
3-methyl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} Butanoic acid;
((1S, 2R) -2- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole-5 -Yl} cyclopropyl) acetic acid;
((1S, 2S) -2- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole-5 -Yl} cyclopropyl) acetic acid;
3-Pyridin-3-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -4H- [1,2,4 ] Triazol-3-yl} -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -tetrazole- 2-yl} -butyric acid;
(2- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,3,4] -oxa-diazol-2-yl } -Cyclopropyl) -acetic acid;
3-phenyl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,3,4] oxadiazole-2 -Yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- [1,3,4] oxadiazol-2-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,3,4 ] Oxadiazol-2-yl} -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1 , 3,4] -oxadiazol-2-yl} -butyric acid;
(2- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -2H-tetrazol-5-yl} -cyclopropyl) -acetic acid;
3-phenyl-4 {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -2H-tetrazol-5-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- 2H-tetrazol-5-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- 2H-tetrazol-5-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -2H-tetrazole-5 Il} -butyric acid;
3-Pyridin-3-yl-4- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -2H-tetrazol-5-yl} -Butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -2H- Tetrazol-5-yl} -butyric acid;
(2- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-3-yl} -cyclopropyl) -acetic acid;
3-phenyl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-3-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- Isoxazol-3-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-3-yl} -Butyric acid;
3-Pyridin-3-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-3-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazole- 3-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- Isoxazol-5-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-5-yl} -Butyric acid;
3-Pyridin-3-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-5-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazole- 5-yl} -butyric acid;
3-phenyl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -1H-pyrazol-3-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- 1H-pyrazol-3-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -1H-pyrazole-3- Il} -butyric acid;
3-Pyridin-3-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -1H-pyrazol-3-yl} -Butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -1H- Pyrazol-3-yl} -butyric acid;
(2- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-5-yl} -cyclopropyl) -acetic acid;
(2- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -1H-pyrazol-3-yl} -cyclopropyl) -acetic acid;
(2- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -thiazol-2-yl} -cyclopropyl) -acetic acid;
3-phenyl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -thiazol-2-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- Thiazol-2-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -thiazol-2-yl} -Butyric acid;
3-Pyridin-3-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -thiazol-2-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -thiazole- 2-yl} -butyric acid;
3-phenyl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazol-1-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- Pyrazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazol-1-yl} -Butyric acid;
3-Pyridin-3-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazol-1-yl} -butyric acid ;
3-Pyridin-3-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazol-1-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazole- 1-yl} -butyric acid;
3-phenyl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- Imidazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -Butyric acid;
3-Pyridin-3-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazole- 1-yl} -butyric acid;
3-phenyl-4- {3- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -isoxazol-5-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {3- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy]- Isoxazol-5-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -isoxazol-5-yl} -Butyric acid;
3-Pyridin-3-yl-4- {3- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -isoxazol-5-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {3- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -isoxazole- 5-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {5- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -2H-pyrazole-3- Il} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {5- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy]- 2H-pyrazol-3-yl} -butyric acid;
3-phenyl-4- {5- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -2H-pyrazol-3-yl} -butyric acid;
3-Pyridin-3-yl-4- {5- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -2H-pyrazol-3-yl} -Butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {5- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -2H- Pyrazol-3-yl} -butyric acid;
3-phenyl-4- [4- (3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propionyl) -imidazol-1-yl] -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- [4- (3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propionyl) -imidazole -1-yl] -butyric acid;
3- (3-Fluoro-phenyl) -4- [4- (3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propionyl) -imidazol-1-yl}- Butyric acid;
3-pyridin-3-yl-4- [4- (3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl-propionyl) -imidazol-1-yl] -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- [4- (3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl-propionyl) -imidazole-1- Yl] -butyric acid;
4- {4- [1-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -3-phenyl-butyric acid ;
3- (2,3-Dihydro-benzofuran-6-yl-4- {4- [1-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl)- Propyl] -imidazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [1-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazole- 1-yl} -butyric acid;
4- {4- [1-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -3-pyridine-3 -Yl-butyric acid;
4- {4- [1-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -3-pyridine-3 -Yl-butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -prop-1-ynyl] -imidazol-1-yl} -3 -Phenyl-butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -Prop-1-ynyl] -imidazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -prop-1-ynyl ] -Imidazol-1-yl} -butyric acid;
4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -prop-1-ynyl] -imidazol-1-yl} -3 -Pyridin-3-yl-butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- 2H-tetrazol-5-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -2H-tetrazole-5 Il} -butyric acid;
3-Pyridin-3-yl-4- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -2H-tetrazol-5-yl} -Butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {2- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -2H- Tetrazol-5-yl} -butyric acid;
2- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-3-yl} -cyclopropyl-acetic acid;
3-phenyl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-3-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- Isoxazol-3-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-3-yl} -Butyric acid;
3-Pyridin-3-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-3-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazole- 3-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- Isoxazol-5-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-5-yl} -Butyric acid;
3-Pyridin-3-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-5-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazole- 5-yl} -butyric acid;
3-phenyl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -1H-pyrazol-3-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- 1H-pyrazol-3-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -1H-pyrazole-3- Il} -butyric acid;
3-Pyridin-3-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -1H-pyrazol-3-yl} -Butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -1H- Pyrazol-3-yl} -butyric acid;
(2- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -isoxazol-5-yl} -cyclopropyl-acetic acid;
(2- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -1H-pyrazol-3-yl} -cyclopropyl) -acetic acid;
(2- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -thiazol-2-yl} -cyclopropyl-acetic acid;
3-phenyl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -thiazol-2-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- Thiazol-2-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -thiazol-2-yl} -Butyric acid;
3-Pyridin-3-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -thiazol-2-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -thiazole- 2-yl} -butyric acid;
3-phenyl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazol-1-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- Pyrazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazol-1-yl} -Butyric acid;
3-Pyridin-3-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazol-1-yl} -butyric acid ;
3-Pyridin-3-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazol-1-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {3- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazole- 1-yl} -butyric acid;
3-phenyl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]- Imidazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -Butyric acid;
3-Pyridin-3-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazole- 1-yl} -butyric acid;
3-phenyl-4- {3- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -isoxazol-5-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {3- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy]- Isoxazol-5-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -isoxazol-5-yl} -Butyric acid;
3-Pyridin-3-yl-4- {3- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -isoxazol-5-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {3- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -isoxazole- 5-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {5- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -2H-pyrazole-3- Il} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {5- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy]- 2H-pyrazol-3-yl} -butyric acid;
3-phenyl-4- {5- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -2H-pyrazol-3-yl} -butyric acid;
3-Pyridin-3-yl-4- {5- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -2H-pyrazol-3-yl} -Butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {5- [2- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -ethoxy] -2H- Pyrazol-3-yl} -butyric acid;
3-phenyl-4- [4- (3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propionyl) -imidazol-1-yl] -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- [4- (3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl-propionyl) -imidazole- 1-yl] -butyric acid;
3- (3-Fluoro-phenyl) -4- [4- (3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl-propionyl) -imidazol-1-yl] -butyric acid ;
3-pyridin-3-yl-4- [4- (3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl-propionyl) -imidazol-1-yl] -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- [4- (3-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl-propionyl) -imidazole-1- Yl] -butyric acid;
4- {4- [1-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -3-phenyl-butyric acid ;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [1-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl- Propyl] -imidazol-1-yl] -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [1-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazole- 1-yl} -butyric acid;
4- {4- [1-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -3-pyridine-3 -Yl-butyric acid;
4- {4- [1-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -3-pyridine-3 -Yl-butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -prop-1-ynyl] -imidazol-1-yl} -3 -Phenyl-butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -Prop-1-ynyl] -imidazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -prop-1-ynyl ] -Imidazol-1-yl} -butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -prop-1-ynyl] -imidazol-1-yl} -3 -Pyridin-3-yl-butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl-prop- 1-ynyl] -imidazol-1-yl} -butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -prop-1-ynyl] -pyrazol-1-yl} -3 -Phenyl-butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -Prop-1-ynyl] -pyrazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl-prop-1-ynyl] -Pyrazol-1-yl} -butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -prop-1-ynyl] -pyrazol-1-yl} -3 -Pyridin-3-yl-butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -prop -1-ynyl] -pyrazol-1-yl} -butyric acid;
4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -pyrazol-1-yl} -3-phenyl-butyric acid ;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -Propenyl] -pyrazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -pyrazole- 1-yl} -butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -pyrazol-1-yl} -3-pyridine-3 -Yl-butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl ] -Pyrazol-1-yl} -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl ] -Pyrazol-1-yl} -butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -imidazol-1-yl} -3-phenyl-butyric acid ;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -Propenyl] -imidazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -imidazole- 1-yl} -butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -imidazol-1-yl} -3-pyridine-3 -Yl-butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl ] -Imidazol-1-yl} -butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -3-phenyl-butyric acid ;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -Propyl] -imidazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazole- 1-yl} -butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -imidazol-1-yl} -3-pyridine-3 -Yl-butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl ] -Imidazol-1-yl] -butyric acid;
4- {4- [3-Hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazol-1-yl} -3-phenyl-butyric acid ;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -Propyl] -pyrazol-1-yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazole- 1-yl} -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl ] -Pyrazol-1-yl} -butyric acid;
4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl] -pyrazol-1-yl} -3-pyridine-3 -Yl-butyric acid;
3- (3-Fluoro-phenyl) -4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -imidazol-1-yl} -Butyric acid;
3-phenyl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -imidazol-1-yl} -butyric acid;
3- (2,3-Dihydro-benzofuran-6-yl) -4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl]- Imidazol-1-yl} -butyric acid;
3-Pyridin-3-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -imidazol-1-yl} -butyric acid ;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -imidazole- 1-yl} -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {4- [3-hydroxy-3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl ] -Pyrazol-1-yl} -butyric acid;
3-Pyridin-3-yl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -pyrazol-1-yl} -butyric acid ;
3-phenyl-4- {4- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propenyl] -pyrazol-1-yl} -butyric acid;
3-hydroxy-4- {3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} -butyric acid;
3-hydroxy-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} -Butanoic acid;
3-Benzo [1,3] dioxol-5-yl-4- {3- [4- (1H-imidazol-2-ylamino) -butyl]-[1,2,4] oxadiazol-5-yl} -Butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [4- (1H-imidazol-2-ylamino) -butyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {3- [4- (2H-pyrazol-3-ylamino) -butyl]-[1,2,4] oxadiazol-5-yl} -Butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [4- (2H-pyrazol-3-ylamino) -butyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {3- [4- (3H-imidazol-4-ylamino) -butyl]-[1,2,4] oxadiazol-5-yl} -Butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [4- (3H-imidazol-4-ylamino) -butyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {3- [3- (6-methylamino-pyridin-2-yl) -propyl]-[1,2,4] oxadiazole-5 -Yl} -butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [3- (6-methylamino-pyridin-2-yl) -propyl]-[1,2,4] oxadiazol-5-yl}- Butyric acid;
4- {3- [3- (6-Ethylamino-pyridin-2-yl) -propyl]-[1,2,4] oxadiazol-5-yl} -3- (3-fluoro-phenyl)- Butyric acid;
3- (3-Fluoro-phenyl) -4- (3- {3- [6- (2-methoxy-ethylamino) -pyridin-2-yl] -propyl}-[1,2,4] oxadiazole -5-yl) -butyric acid;
3- (3-Fluoro-phenyl) -4- (3- {3- [6- (3-methoxy-propylamino) -pyridin-2-yl] -propyl}-[1,2,4] oxadiazole -5-yl) -butyric acid;
3- (3-Fluoro-phenyl) -4- (3- {3- [6- (2,2,2-trifluoro-ethylamino) -pyridin-2-yl] -propyl}-[1,2, 4] oxadiazol-5-yl) -butyric acid;
3- (3-Fluoro-phenyl) -4- {3- [3- (5-oxo-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1 , 2,4] oxadiazol-5-yl} -butyric acid;
4- {3- [3- (5,5-Dimethyl-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] oxadiazole -5-yl} -3- (3-fluoro-phenyl) -butyric acid;
4- {3- [3- (5,5-difluoro-5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) -propyl]-[1,2,4] oxadiazole -5-yl} -3- (3-fluoro-phenyl) -butyric acid; and
3- (1,3-Benzodioxol-5-yl) -4- {3-[(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethoxy) methyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid may also be included.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relates to a group of compounds of formula I as described above.
In another embodiment of the invention, ring A:

Is heteroaryl substituted with one or more substituents selected from lower alkyl, alkynyl, alkenyl, halogen, alkoxy, hydroxy, cyano, amino, alkylamino, dialkylamino or methylsulfonamide. In particular, some examples of heteroaryl include oxadiazole, pyridine, pyrimidine, imidazole, thiadiazole, triazole, tetrazole, pyrazole, isoxazole and thiazole.

  The following formula:

Another embodiment of the present invention is a heterocycle system having at least one nitrogen atom:

Wherein Z _a is H, alkyl, alkoxy, hydroxy, amine, alkylamine, dialkylamine, carboxyl, alkoxycarbonyl, hydroxyalkyl, halogen or haloalkyl, and R ¹ is H, alkyl, alkoxyalkyl, Is acyl, haloalkyl or alkoxycarbonyl]. In particular, some examples include pyridylamino, imidazolylamino, morpholinopyridine, tetrahydronaphthyridine, oxazolylamino, thiazolylamino, pyrimidinylamino, quinoline, tetrahydroquinoline, imidazopyridine, benzimidazole, pyridone or quinolone.

  The following heteroaryl:

Includes the aforementioned cyclic systems.
In the heterocycle derived from pyridyl, the substituents X ₄ and X ₅ are H, alkyl, branched alkyl, alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino, alkoxy, aryloxy, alkoxyalkyl, hydroxy, Selected from the group consisting of cyano or acylamino groups.

In another embodiment of the invention, the substituents X ₄ and X ₅ can be methyl, methoxy, amine, methylamine, trifluoromethyl, dimethylamine, hydroxy, chloro, bromo, fluoro and cyano. X ₆ may preferably be H, alkyl, hydroxy, halogen, alkoxy and haloalkyl. Also, the pyridyl ring can be condensed with a 4-8 membered ring and may be saturated or unsaturated. Examples of these ring systems include tetrahydronaphthyridine, quinoline, tetrahydroquinoline, azaquinoline, morpholinopyridine, imidazopyridine and the like. Monocyclic ring systems such as imidazole, thiazole, oxazole, pyrazole may contain amino or alkylamino substituents at any position of the ring.

In another embodiment of the invention, when Z _{1 of} formula I is CO or SO ₂ , the A ¹ -Z ₂ linkage of formula I is a ring system derived from a heterocycle: pyridine, imidazole, thiazole, oxazole, benz Including imidazole and imidazopyridine.

Other heterocycles for A ¹ -Z ₂ of the present invention have the following formula:

Wherein X ₄ is as described above.
In another embodiment, Y ³ or Y ⁴ is phenyl, benzofuran, benzothiophene, indole, quinoline, isoquinoline, benzimidazole, benzoxazole, 1,3-benzodioxole, 1,4-benzodioxan, benzopyran, Selected from quinolone, imidazopyridine, tetrahydro-quinoline, benzotriazole, dihydroindole, dihydrobenzofuran, furan, thiophene, phenyl, oxazole, thiazole, isoxazole, pyrazole, imidazole, pyrrole, pyridine, pyrimidine, pyridone, triazole, thiadiazole, etc. An aryl or heteroaryl group. The aryl system may be substituted at one or more positions with alkyl, alkoxy, hydroxy, cyano, halogen or haloalkyl.

In another embodiment of the invention, Y ³ or Y ⁴ may be an amine, alkylamine, acylamine, aminosulfone (NHSO ₂ R), arylamine, alkoxyalkylamine, aralkylamine or heterocyclic amine. .

In another embodiment of the invention, Y ³ together with Y ⁴ is a 3-8 membered monocyclic or 7-11 membered bicyclic ring, B:

And ring B may contain one or more double bonds and contain one or more heteroatoms or functional groups selected from O, NR ^g , S, CO or SO ₂ Optionally substituted with one or more substituents selected from alkyl, haloalkyl, halogen, haloalkyl, alkoxy, alkyne, cyano, alkylsulfone, sulfonamido, carboalkoxy and carboxyalkyl, where R ^g is selected from the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, aryl, heteroaryl, aralkyl and carboxyalkyl).

In another embodiment of the invention, X together with Y ³ is a 3-7 membered monocyclic ring, C:

And ring C may contain one or more double bonds and contain one or more heterocycles or functional groups selected from O, NR ^g , S, CO or SO ₂ Optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, alkoxy, haloalkyl, hydroxyalkyl or alkoxyalkyl, wherein R ^g is H, alkyl, haloalkyl, Selected from the group consisting of alkoxyalkyl, aryl, heteroaryl, aralkyl and carboxyalkyl).

The present invention further relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I.
The present invention also provides, Arufabuibeta ₃ integrin and / or Arufabuibeta relates _integrin selectively inhibit or method of antagonizing a well ,, bone resorption in particular, periodontal disease, osteoporosis, humoral hypercalcemia of malignancy, Paget's disease , Tumor metastasis, solid tumor growth (neoplasm), angiogenesis (such as tumor angiogenesis), retinopathy (such as macular degeneration and diabetic retinopathy), arthritis (such as rheumatoid arthritis), smooth muscle cells Wherein said therapeutically effective amount of a compound of formula I is administered together with a pharmaceutically acceptable carrier to obtain such an inhibitory effect. About. Furthermore, it is advantageous to administer the compound in Arufabuibeta ₃ and / or Arufabuibeta ₅ is selective, and it has been found to be beneficial in such selectivity reduces unwanted side effects.

The following is a list of definitions of various terms used herein.
As used herein, the terms “hydrocarbon” and “hydrocarbyl” refer to organic compounds or radicals composed primarily of carbon and hydrogen elements. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups (alkaryl, alkenearyl, alkynearyl, etc.). Unless otherwise specified, these moieties preferably contain 1 to 20 carbon atoms.

  As used herein, the term “alkyl” or “lower alkyl” refers to a straight or branched hydrocarbon radical having from about 1 to about 10 carbon atoms, preferably from 1 to about 6 carbon atoms. Show. Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl and the like.

  As used herein, the term “alkenyl” refers to a straight or branched hydrocarbon having at least one carbon-carbon double bond, consisting of 2 to about 20, preferably 2 to about 12 carbon atoms. Includes radicals. More preferred alkyl radicals are “lower alkenyl” radicals having 2 to about 10 carbon atoms. In another embodiment, the alkenyl radical is a lower alkenyl radical having 2 to about 6 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The terms “alkenyl” and “lower alkenyl” include radicals having “cis” and “trans” configurations, in other words, “E” and “Z” configurations.

  As used herein, the term “alkynyl” refers to a straight or branched carbon or hydrocarbon radical having from 2 to about 20 carbon atoms, or preferably from 2 to about 12 carbon atoms. More preferred alkynyl radicals are “lower alkynyl” radicals having 2 to about 10 carbon atoms. In another embodiment, the alkynyl radical is a lower alkynyl radical having 2 to about 6 carbon atoms. Examples of such radicals include propargyl, butynyl and the like.

  As used herein, the term “cycloalkyl” means a saturated or partially unsaturated cyclic hydrocarbon radical containing 3 to about 8 carbon atoms, preferably 4 to about 6 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl and the like.

  As used herein, the term “aryl” refers to an aromatic ring system composed of one or more aromatic rings. Preferred aryl groups are those consisting of 1, 2 or 3 aromatic rings. This term includes aromatic radicals such as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl and the like.

  The term “substituted aryl” moiety described herein is an aryl moiety that is substituted with at least one atom, wherein one atom of the carbon chain is nitrogen, oxygen, silicon, phosphorus, boron, sulfur or Includes a moiety substituted with a heteroatom such as a halogen atom. These substituents are halogen, heterocyclo, hydrocarbyloxy (alkoxy, alkeneoxy, alkyneoxy, aryloxy, hydroxy, protected hydroxy, etc.), keto, acyl, acyloxy, nitro, amino, amide, nitro, cyano, thiol, ketal , Acetals, esters and ethers.

  As used herein, the term “cyano” has the following formula:

It is represented by the radical of
As used herein, the terms “hydroxy” and “hydroxyl” are synonymous and have the following formula:

It is represented by the radical of
As used herein, the term “lower alkylene” or “alkylene” refers to a divalent straight chain or branched saturated hydrocarbon radical of 1 to about 6 carbon atoms.

As used herein, the term “alkoxy” refers to a straight or branched chain comprising a radical of the formula —OR ^20, where R ²⁰ is an alkyl group as defined above. Indicates a radical containing oxy. Examples of included alkoxy groups include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy, t-butoxy and the like.

  As used herein, the term “arylalkyl” or “aralkyl” refers to the following formula:

Wherein R ²¹ is aryl as defined above and R ²² is alkylene as defined above. Examples of aralkyl groups include benzyl, pyridylmethyl, naphthylpropyl, phenethyl and the like.

  As used herein, the term “nitro” has the following formula:

Represented by the radical of
As used herein, the term “halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

  As used herein, the term “haloalkyl” refers to an alkyl group, as defined above, substituted at one or more carbon atoms with one or more identical or different halo groups. Examples of haloalkyl groups include trifluoromethyl, dichloroethyl, fluoropropyl, and the like.

As used herein, the term “carboxyl” or “carboxy” refers to a radical of the formula —COOH.
As used herein, the term “carboxyl ester” is selected from the group consisting of the formula —COOR ^23, where R ²³ is as defined above, H, alkyl, aralkyl, or aryl. ).

  As used herein, the term “carboxyl derivative” has the following formula:

Wherein Y ⁶ and Y ⁷ are independently selected from the group consisting of O, N or S, and R ²³ is from the group consisting of H, alkyl, aralkyl or aryl as defined above. Selected radicals).

As used herein, the term “amino” refers to the group —NT ² T ^3, where T ² and T ³ are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, aryl, or heteroaryl. Show). T ² and T ³ may form a monocyclic or polycyclic amino ring. The term “cyclic amino” refers to 3 to 8 atoms (of which at least one is nitrogen but may contain other heteroatoms such as oxygen, silicon, phosphorus, boron, sulfur or halogen). Including saturated heterocyclic radicals having

  As used herein, the term “alkylsulfonyl” or “alkylsulfone” has the following formula:

Wherein R ²⁴ is alkyl as defined above.
As used herein, the term “alkylthio” refers to a radical of the formula —SR ^24, where R ²⁴ is alkyl as defined above.

  As used herein, the term “sulfonic acid” has the following formula:

Wherein R ²⁵ is alkyl as defined above.
As used herein, the term “sulfonamide” or “sulfonamido” refers to the following formula:

Wherein R ⁷ and R ⁸ are as defined above.
As used herein, the term “fused aryl” refers to an aromatic ring, such as an aryl group as defined above, fused to one or more phenyl rings. Included within the term “fused aryl” are naphthyl radicals and the like.

  As used herein, the term “monocyclic heterocycle” or “monocyclic heterocyclic” refers to 4 to about 12 atoms, preferably 5 to about 10 atoms. A monocyclic ring containing 1 to 3 of these atoms are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, but when two or more different heteroatoms are present , Provided that at least one of the heteroatoms is nitrogen). Representative examples of such monocyclic heterocycles are imidazole, furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole, thiazole, thiadiazole and the like.

  As used herein, the term “fused monocyclic heterocycle” refers to a monocyclic heterocycle as defined above fused to benzene. Examples of such fused monocyclic heterocycles include benzofuran, benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazole, and the like.

  As used herein, the term “methylenedioxy”, the following formula:

And the term “ethylenedioxy” refers to the following formula:

The radical of
As used herein, the term “4- to 12-membered, dinitrogen-containing heterocycle” refers to the following formula:

Wherein R is 1 or 2, and R ¹⁹ is H, alkyl, aryl or aralkyl, more preferably a 4-9 membered ring including a ring such as imidazoline. .

  As used herein, the term “5-membered, optionally substituted heteroaromatic ring” includes, for example, the following formula:

And a “5-membered heteroaromatic ring fused to phenyl” refers to such a “5-membered heteroaromatic ring” fused to phenyl. A typical example of such a 5-membered heteroaromatic ring fused to phenyl is benzimidazole.

As used herein, the term “bicycloalkyl” refers to a bicyclic hydrocarbon radical containing 6 to about 12 carbon atoms, saturated or partially unsaturated.
As used herein, the term “acyl” has the following formula:

In which R ²⁶ is alkyl, alkenyl, alkynyl, aryl or aralkyl, and may be optionally substituted as defined above. Such radicals include groups such as acetyl and benzoyl.

  As used herein, the term “thio” has the following formula:

The radical of
As used herein, the term “sulfonyl” has the following formula:

Wherein R ²⁷ is alkyl, aryl or aralkyl as defined above.
As used herein, the term “haloalkylthio” refers to a radical of the formula —S—R ^28, where R ²⁸ is haloalkyl as defined above.

  As used herein, the term “aryloxy” has the following formula:

Wherein R ²⁹ is aryl as defined above.
As used herein, the term “acylamino” has the following formula:

Wherein R ³⁰ is alkyl, aralkyl or aryl as defined above.
As used herein, the term “amide” has the following formula:

The radical of
As used herein, the term “alkylamino” refers to a radical of the formula —NHR ³² where R ³² is alkyl as defined above.

As used herein, the term “dialkylamino” refers to a radical of the formula —NR ³³ R ^34, where R ³³ and R ³⁴ are the same or different alkyl groups as defined above. Indicates.

  As used herein, the term “trifluoromethyl” has the following formula:

The radical of
As used herein, the term “trifluoroalkoxy” has the following formula:

Wherein R ³⁵ is a bond or an alkylene as defined above.
As used herein, the term “alkylaminosulfonyl” or “aminosulfonyl” has the following formula:

Wherein R ³⁶ is alkyl as defined above.
As used herein, the term “alkylsulfonylamino” or “alkylsulfonamide” refers to the following formula:

Wherein R ³⁶ is alkyl as defined above.
As used herein, the term “trifluoromethylthio” has the following formula:

The radical of
As used herein, the term “trifluoromethylsulfonyl” refers to the following formula:

The radical of
As used herein, a “4- to 12-membered, one-nitrogen-containing monocyclic or bicyclic ring” is a saturated or partially unsaturated 4- to 12-membered monocyclic ring in which one atom is nitrogen or Bicyclic rings (more preferably 4 to 9 membered rings) are shown. Such a ring may further comprise a heteroatom selected from nitrogen, oxygen or sulfur. Included in this group are morpholine, piperidine, piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene, and the like.

  As used herein, the term “benzyl” has the following formula:

The radical of
As used herein, the term “phenethyl” refers to the following formula:

The radical of
As used herein, the term “4- to 12-membered mono-nitrogen, mono-sulfur or mono-oxygen-containing heterocycle” means that at least one atom is nitrogen and at least one atom is oxygen or sulfur. And a ring composed of 4 to 12 atoms (more preferably 4 to 9 atoms). Included in this definition are rings such as thiazoline.

  As used herein, the term “arylsulfonyl” or “arylsulfone” has the following formula:

Wherein R ³⁷ is aryl as defined above.
As used herein, the term “alkyl sulfoxide” or “aryl sulfoxide” refers to the following formula:

Wherein R ³⁸ is alkyl or aryl as defined above, respectively.
As used herein, the term “arylthio” has the following formula:

In which R ⁴² is aryl as defined above.
As used herein, the term “monocyclic heterocyclic thio” refers to the following formula:

Wherein R ⁴³ is a monocyclic heterocyclic radical as defined above.
As used herein, the terms “monocyclic heterocyclic sulfoxide” and “monocyclic heterocyclic sulfone” each represent the following formula:

Wherein R ⁴³ is a monocyclic heterocyclic radical as defined above.
As used herein, the term “alkylcarbonyl” refers to the following formula:

Wherein R ⁵⁰ is alkyl as defined above.
As used herein, the term “arylcarbonyl” refers to the following formula:

In which R ⁵¹ is aryl as defined above.
As used herein, the term “alkoxycarbonyl” has the following formula:

Wherein R ⁵² is alkoxy as defined above.
As used herein, the term “aryloxycarbonyl” refers to the following formula:

In which R ⁵¹ is aryl as defined above.
As used herein, the term “haloalkylcarbonyl” refers to the following formula:

Wherein R ⁵³ is haloalkyl as defined above.
As used herein, the term “haloalkoxycarbonyl” has the following formula:

Wherein R ⁵³ is haloalkyl as defined above.
As used herein, the term “alkylthiocarbonyl” refers to the following formula:

Wherein R ⁵⁰ is alkyl as defined above.
As used herein, the term “arylthiocarbonyl” refers to the following formula:

In which R ⁵¹ is aryl as defined above.
As used herein, the term “acyloxymethoxycarbonyl” refers to the following formula:

Wherein R ⁵⁴ is acyl as defined above.
As used herein, the term “arylamino” refers to a radical of the formula R ⁵¹ —NH—, wherein R ⁵¹ is aryl as defined above.

As used herein, the term “acyloxy” refers to a radical of the formula R ⁵⁵ —O—, wherein R ⁵⁵ is acyl as defined above.
As used herein, the term “alkenylalkyl” has the formula R ⁵⁰ —R ⁵⁷ —, where R ⁵⁰ is alkenyl as defined above, and R ⁵⁷ is as defined above. Radicals which are alkylene).

As used herein, the term “alkenylene” refers to a linear hydrocarbon radical of 1 to about 8 carbon atoms containing at least one double bond.
As used herein, the term “alkoxyalkyl” refers to the formula R ⁵⁶ —R ⁵⁷ —, where R ⁵⁶ is alkoxy as defined above, and R ⁵⁷ is as defined above. Radicals which are alkylene).

As used herein, the term “alkynylalkyl” refers to the formula R ⁵⁹ —R ⁶⁰ —, where R ⁵⁹ is alkynyl as defined above, and R ⁶⁰ is as defined above. Radicals which are alkylene).

As used herein, the term “alkynylene” refers to a divalent alkynyl radical of 1 to about 6 carbon atoms.
As used herein, the term “allyl” refers to a radical of the formula —CH ₂ CH═CH ₂ .

As used herein, the term “aminoalkyl” refers to a radical of the formula H ₂ N—R ^61, where R ⁶¹ is alkylene as defined above.
As used herein, the term “benzoyl” refers to an aryl radical, C ₆ H ₅ —CO—.

As used herein, the term “carboxamide” or “carboxamido” refers to a radical of the formula —CO—NH ₂ .
As used herein, the term “carboxyalkyl” refers to a radical of the formula HOOC-R ^62, where R ⁶² is alkylene as defined above.

As used herein, the term “carboxylic acid” refers to the radical —COOH.
As used herein, the term “ether” is a radical of the formula R ⁶³ —O—, wherein R ⁶³ is selected from the group consisting of alkyl, aryl and heteroaryl as defined above. Indicates.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.
The terms “heterocyclo” and “heterocyclic” are 3 to 10 members (at least one carbon atom and not more than 9 independently selected from carbon, nitrogen, sulfur and oxygen). Means saturated, partially unsaturated and unsaturated heteroatom-containing cyclic radicals containing further members). This radical may be, for example, the following structural formula:

Wherein Z, Z ¹ , Z ² or Z ³ is C, S, O or N; provided that one of Z, Z ¹ , Z ² or Z ³ is an atom other than carbon. , When bonded to another Z atom through a double bond, or when bonded to another O or S atom, not O or S). Furthermore, it may be considered that any substituent is bonded to Z, Z ¹ , Z ² or Z ³ (only when each is C).

  Examples of saturated heterocyclic radicals are 3 to 8 membered saturated heteromonocyclic groups containing 1 to 4 nitrogen atoms (eg pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl etc.); 1 to 2 oxygen atoms and 3 to 8 membered saturated heteromonocyclic groups containing 1 to 3 nitrogen atoms (eg morpholinyl etc.); 3 to 8 membered saturated hetero containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms Monocyclic groups (eg thiazolidinyl etc.) are included. Examples of partially unsaturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.

  As used herein, a “substituted heterocycle” moiety refers to a heterocycle moiety substituted with at least one atom (wherein one carbon chain atom is nitrogen, oxygen, silicon, phosphorus, boron, sulfur or Including a moiety substituted with a heteroatom such as a halogen atom). These substituents are halogen, heterocycle, hydrocarbyloxy (alkoxy, alkeneoxy, alkyneoxy, aryloxy, hydroxy, protected hydroxy, etc.), keto, acyl, acyloxy, nitro, amino, amide, nitro, cyano, Includes thiols, ketals, acetals, esters and ethers.

  As used herein, the term “haloalkylsulfonyl” has the following formula:

Wherein R ⁶⁴ is haloalkyl as defined above.
As used herein, the term “heteroaryl” refers to an aryl radical containing at least one heteroatom.

As used herein, the term “hydroxyalkyl” refers to a radical of the formula HO—R ⁶⁵ —, where R ⁶⁵ is alkylene as defined above.
As used herein, the term “keto” refers to a carbonyl group bonded to two carbon atoms.

As used herein, the term “lactone” refers to an anhydrous cyclic ester produced by intramolecular condensation of a hydroxy acid with the elimination of water.
As used herein, the term “olefin” refers to an unsaturated hydrocarbon radical of the C _n H _2n type.

As used herein, the term “sulfone” refers to a radical of the formula R ⁶⁶ —SO ₂ —.
As used herein, the term “thioalkyl” refers to a radical of the formula R ⁷⁷ —S—, wherein R ⁷⁷ is alkyl as defined above.

As used herein, the term “thioether” refers to a radical of the formula R ⁷⁸ —S—, where R ⁷⁸ is alkyl, aryl or heteroaryl.
As used herein, the term “trifluoroalkyl” refers to an alkyl radical as defined above substituted with three halo radicals as defined above.

As used herein, the term “composition” means a product formed by mixing or combining more than one element or component.
As used herein, “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition or vehicle (liquid or solid extender, diluent, excipient) involved in the transport or transport of chemical agents. Means form, solvent or encapsulating material).

The term “therapeutically effective amount” means the amount of a drug or pharmaceutical agent that can induce a biological or medical response of a tissue, organ or animal that is sought by a researcher or clinician.
As used herein, the term “treatment” refers to the medical management of a subject (eg, an animal or a human) intended to prevent, cure, stabilize or ameliorate a particular symptom or condition. The terms include active treatment (ie, treatment that specifically aims to improve the disease), expected treatment (ie, treatment aimed at reducing symptoms rather than cure of the disease), preventive treatment (ie, prevention of disease). Treatment aimed at), and supportive treatment (treatment performed to supplement other specific treatments aimed at improving disease). The term “treatment” also includes symptomatic treatment (ie, treatment performed on constitutional symptoms of the disease). With the compounds of the present invention, “treating” a condition refers to an animal, a cell, a lysate or extract derived from a cell, or a molecule derived from a cell, alone or in combination, and an appropriate Administering by any means.

The following is a list of abbreviations and corresponding meanings used interchangeably herein.
¹ H-NMR = proton nuclear magnetic resonance AcOH = acetic acid BOC = tert -butoxycarbonyl BuLi = butyllithium Cat. = Catalyst amount CDI = Carbonyldiimidazole CH ₂ Cl ₂ = Dichloromethane CH ₃ CN = Acetonitrile CH ₃ I = Iodomethane CHN analysis = Elemental analysis of carbon / hydrogen / nitrogen CHNCl analysis = Elemental analysis of carbon / hydrogen / nitrogen / chlorine CHNS analysis = Elemental analysis of carbon / hydrogen / nitrogen / sulfur DEAD = diethyl azodicarboxylate DIAD = diisopropyl azodicarboxylate DI water = deionized water DMA = N , N -dimethylacetamide DMAC = N, N-dimethylacetamide DMF = N , N - dimethylformamide EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide Et = ethyl Et ₂ O = diethyl ether Et ₃ N = triethylamine EtOAc = ethyl acetate EtOH = ethanol FAB MS = fast atom bombardment mass spectrometry
g = gram (same as other than 1g)
HOBT = 1-hydroxybenzotriazole hydrate HPLC = high performance liquid chromatography i-Pr = isopropyl i-Prop = isopropyl K ₂ CO ₃ = potassium carbonate KMnO ₄ = potassium permanganate KOH = potassium hydroxide KSCN = potassium thiocyanate L = liter LiOH = lithium hydroxide Me = methyl MeOH = methanol mg = milligram MgSO ₄ = magnesium sulfate ml = milliliter mL = milliliter MS = mass spectrometry NaH = sodium hydride NaHCO ₃ = sodium bicarbonate NaOH = sodium hydroxide NaOMe = sodium methoxide NH ₄ ⁺ NCO ₂ ^over = ammonium formate NMR = nuclear magnetic resonance Pd = palladium Pd / C = palladium Ph = phenyl Pt = plastics on carbon Tina Pt / C = platinum on carbon RPHPLC = reverse phase high performance liquid chromatography RT = room temperature t-BOC = tert -butoxycarbonyl TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMS = trimethylsilyl Δ = reaction mixture Heating The series of compounds can exist in various isomeric forms, and all such isomeric forms are included. Tautomeric forms are also included as well as pharmaceutically acceptable salts of these isomers and tautomers.

In the structural and chemical formulas herein, a bond drawn across a ring bond can be bonded to any atom that can be bonded to the ring.
The term “pharmaceutically acceptable salt” refers to a salt prepared by contacting a compound of Formula I with certain acids, whose anions are generally considered suitable for human consumption. For use as a medicament, the salts of the compounds of the invention are non-toxic "pharmaceutically acceptable salts". Salts encompassed within the term “pharmaceutically acceptable salts” herein refer to non-toxic salts of the compounds of the present invention and these salts generally are obtained by reacting the free base with a suitable organic or inorganic acid. It is manufactured. Typical salts include the following: benzene sulfonate, hydrobromide and hydrochloride. In addition, when the compounds of the present invention have an acid moiety, suitable pharmaceutically acceptable salts of these compounds are alkali metal salts (eg, sodium or potassium salts), alkaline earth metals (eg, calcium salts or magnesium) Salts), and salts formed with suitable organic ligands (eg, quaternary ammonium salts). All of these pharmaceutically acceptable salts can also be prepared by conventional methods (further examples of pharmaceutically acceptable salts are described in “Berge et al., J Pharm. Sci., 66 (1), 1-19 (1977)).

  The compounds of the invention may have chiral centers and may exist as racemates, racemic mixtures, diastereomeric mixtures and each single diastereomer or enantiomer, and all isomeric forms are included in the invention . Thus, when a compound is chiral, each enantiomer or diastereomer (substantially lacking the enantiomer) is within the scope of the invention, and all enantiomeric or diastereomeric mixtures are also within the scope of the invention. Included in the range. Also within the scope of the invention are polymorphs, hydrates or other modifications of the compounds of the invention.

  The present invention includes within its scope prodrugs of the compounds of this invention. In general, those prodrugs will be functional derivatives of the compounds of this invention that are readily convertible in vivo into the required compound. For example, prodrugs of carboxylic acids may contain esters, amides, or ortho-position esters. Thus, in the methods of treatment of the present invention, the term “administration” is converted to a compound of formula I in vivo after administration to a patient, although not specifically disclosed, or to a patient, although not specifically disclosed herein. It is intended to include treatment of the various conditions described above with compounds. Conventional methods for selecting and producing suitable prodrug derivatives are described, for example, in the document “Design of Prodrugs”, edited by H. Bundgaard, Elsevier, 1985 ”. Is hereby incorporated by reference in its entirety. Metabolites of these compounds include the active forms that occur when the compounds of the invention are placed in a biological environment.

respect Arufabuibeta ₃ and / or Arufabuibeta ₅ integrins selective inhibition or antagonism, compounds of the present invention, conventional pharmaceutically acceptable carriers, as unit dose formulations containing carriers, adjuvants and vehicles orally, parenterally, or The compounds can be administered by inhalation or topically. As used herein, the term “parenteral” includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, submuscular infusion or intraperitoneal administration.

  The compounds of this invention are administered by any suitable method of administration, in the form of a pharmaceutical composition suitable for such a route, and in a dose effective for the treatment intended. The therapeutically effective amounts of these compounds required to prevent conditions that prevent medical treatment or to prevent or treat their progression are preclinical or clinical well-known in the medical field. Can be readily ascertained by one of ordinary skill in the art using standard methods.

Accordingly, the present invention is a method of treating a condition that was involved which selectively inhibit or antagonize Arufabuibeta ₃ and / or Arufabuibeta ₅ cell surface receptors, the treatment of the group of compounds represented by the formula One or more of the compounds is a non-toxic, pharmaceutically acceptable carrier and / or diluent or adjuvant (collectively referred to herein as “carrier” material). As defined above, as well as other active ingredients if necessary. Furthermore particularly, the present invention is greater than the alpha _IIb beta ₃ or Arufabuibeta ₆ integrin receptor provides a method for selective antagonism to Arufabuibeta ₃ or Arufabuibeta ₅ cell surface receptors. The present invention most preferably suppresses bone resorption, treats osteoporosis, suppresses malignant humoral hypercalcemia, treats Paget's disease, suppresses tumor metastasis, and neoplasm (solid tumor growth) Suppresses angiogenesis (including tumor angiogenesis), treats retinopathy (including macular degeneration and diabetic retinopathy), suppresses arthritis, psoriasis and periodontal disease, and smoothes Methods for inhibiting muscle cell migration (including restenosis) are provided.

  Based on standard laboratory techniques and methods well known and appreciated by those skilled in the art and comparisons with compounds of known efficacy, the compounds of formula I are used in the treatment of patients suffering from the above mentioned pathologies can do. Choosing the optimal compounds of the invention does not exceed the competence of ordinary technicians, and the choice depends on a variety of factors, including evaluation of results obtained with standard assays and animal models Those skilled in the art will recognize that.

  Treatment of a patient suffering from any of the above medical conditions is in terms of controlling the condition or in that the patient's survival rate is improved from what would be expected without such treatment, Administering to such patients a therapeutically effective amount of a compound of formula I. In the present specification, the term “suppression” of a state means delaying, blocking, inhibiting, or stopping the progress of the state, and does not necessarily mean that the state is completely removed. do not do. Improving the survival rate of a patient is not only remarkably effective for the patient itself, but may be considered that the state is controlled to some extent effectively.

As mentioned above, the compounds of the present invention can be used in a variety of biological, prophylactic or therapeutic fields. for the prevention or treatment for any disease state or condition Arufabuibeta ₃ and / or Arufabuibeta ₅ integrin impact is exerted, these compounds are expected to be useful.

  The dosage regimen of the compounds and / or compositions containing these compounds depends on various factors (patient type, age, weight, sex and disease state; severity of the disease state; mode of administration; and the specific used Based on the activity of the compound. Therefore, its usage and dosage can vary widely. Dosage levels on the order of about 0.01 mg / kg to about 100 mg / kg body weight per day are effective in treating the above conditions.

  The oral dose of the compound of the present invention is about 0.01 mg to about 100 mg (kg / kg / day), preferably 0.01 to 10 mg / kg, per kg body weight per day when used in view of the above effects. / Day, most preferably in the range of 0.1 to 1.0 mg / kg / day. In the case of oral administration, the dosage for the patient to be treated is adjusted according to the symptoms, and the composition is preferably 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, Provided in the form of tablets containing 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200 or 500 milligrams of active ingredient. The medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 mg of the active ingredient. For intravenous injection, the most preferred dose will be in the range of about 0.1 to 10 mg / kg / min during a constant rate infusion. Conveniently, the compound of the invention can be administered in a single daily dose, or the total daily dose can be administered in two, three or four divided doses per day. Is possible. In addition, suitable compounds of the present invention can be obtained by intranasal use by topical use of a suitable intranasal vehicle, or by transdermal skin patch excipients, as is well known to those skilled in the art. It can be administered by a transdermal route by dermal use. To administer in the form of a transdermal delivery system, the daily dosage will, of course, be continuous rather than intermittent in terms of dosage and administration.

  For administration to mammals in need of such treatment, it is usual to combine a therapeutically effective amount of a series of compounds with one or more adjuvants appropriate for the desired route of administration. For suitable administration, a series of compounds are combined with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium salts of phosphoric acid and sulfuric acid and It may be mixed with calcium salts, gelatin, gum arabic, sodium alginate, polyvinyl pyrrolidone and / or polyvinyl alcohol, and may be tableted or encapsulated. The compounds may also be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Other adjuvants and modes of administration are also widely known in the pharmaceutical field.

  Pharmaceutical compositions useful in the present invention may be subjected to conventional pharmaceutical operations such as sterilization and / or contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, and the like. May be.

General synthetic procedures for preparing compounds useful in the present invention are outlined in Reaction Schemes 1-42. The description of various aspects of the invention and the practical method are both described in appropriate terms. The following reaction schemes and examples are merely illustrative of the invention and are not intended to limit the invention in terms of scope or spirit. One skilled in the art will readily appreciate that the compounds of the invention can be synthesized using known variations of the conditions and processes described in these reaction schemes and examples.
Reaction scheme 1

Reaction scheme 1
Preparation of a compound of formula A ₁₃ by reacting an intermediate of formula A ₁₁ with a compound of formula A ₁₂ wherein ring A is preferably a 6-membered heteroaryl or a bicyclic heteroaryl can do. For example, when Z ₃ is OH, SH or NHR, preferably using a base such as sodium hydride or potassium hydride in a solvent such as dimethyl sulfoxide or DMF, A ₁₂ is converted to A ₁₁ (Z ₄ = Br Or it may be alkylated with OMs). These reactions may preferably be performed at 0 ° C. to about 40 ° C. Also, when both Z ₃ and Z ₄ are OH, ether formation to product A ₁₃ may be performed utilizing a Mitsunobu reaction. This reaction is preferably carried out in a solvent such as DMF, methylene chloride, THF, and triarylphosphine (such as triphenylphosphine) and azodicarboxylate (diethylazodicarboxylate, di-tert-butylazodicarboxylate, diisopropyl Azodicarboxylate, etc.). Target compounds A ₁₃ containing carboxamide (CONH) can also be synthesized according to standard coupling conditions when Z ₃ has a carboxylic acid and Z ₄ is an amine.

Furthermore, starting from the compound of general formula A _14, it is also possible to prepare a compound of formula A _13. For example, when Z ₅ in A ₁₄ is NH ₂ , a cyclic or acyclic guanidide-containing compound of formula A ₁₃ can be prepared using, for example, the methodology described in US Pat. Nos. 5,852,210 and 5,773,646. Can also be synthesized. Similarly, a compound of the formula _{A 14 (Z 5 = CHO)} , was treated by amino-containing heteroaromatic ring (such as 2-aminopyridine), can also be obtained Compound _{A 13} targets. This reaction may preferably be carried out by a reductive amination method using a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride.

  3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1 , 2,4-oxadiazol-5-yl} butanoic acid:

Step 1 Diethyl-2- (1,3-benzodioxol-5-yl) -4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylate:
According to the method of the document “Brown, E .; Dhal, R .; Papin, N. Tetrahedron, 1995, 51, 13061-13072”, piperonal (22.5 g, 150 mmol), ethyl acetoacetate (38.24 ml, 300 mmol) and Piperidine (1.5 ml) was mixed in a 500 ml round bottom flask and stirred at room temperature. After 72 hours, the mixture had solidified and the mixture was recrystallized with ethanol to give 42.4 g of product (72%). ¹ H NMR (DMSO-d ₆ ) δ 6.95 (m, 1H), 6.8 (m, J = 7.5 Hz, 1H), 6.71 (m, J = 7.5 Hz, 1H), 5.97 (s, 2H), 4.9 ( s, 1H), 4.0-3.7 (m, 6H), 3.25 (d, J = 11 Hz, 1H), 2.9 (d, J = 14 Hz, 1H), 2.35 (d, J = 14 Hz, 1H), 1.23 (s, 3H), 1.0 (t, 3H), 0.92 (t, 3H).

Step 2 3- (1,3-Benzodioxol-5-yl) pentanedioic acid:
Diethyl-2- (1,3-benzodioxol-5-yl) -4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylate (19 g) was added to ethanol (140 ml) and water. Suspended in aqueous sodium oxide (50%, 270 ml). The mixture was heated at reflux for 1 hour. After the mixture was cooled to room temperature, ethanol was removed under reduced pressure. Next, concentrated hydrochloric acid was added until pH 1 while maintaining the temperature at 50 ° C. or lower. This mixture was filtered. The solid was washed with ether. Two layers separated. The aqueous layer was extracted with ether (3 times). The ether layers were combined, dried and concentrated to give the product. ¹ H NMR (DMSO-d ₆ ) δ 12.06 (br s, 2H), 6.88-6.68 (m, 3H), 5.98 (s, 2H), 3.4-3.3 (m, 1H), 2.62-2.42 (m, 4H ).

Step 3 4- (1,3-Benzodioxol-5-yl) dihydro-2H-pyran-2,6- (3H) -dione:
3- (1,3-benzodioxol-5-yl) pentanedioic acid (2 g, 7.9 mmol) was suspended in acetic anhydride (50 ml) and refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature and then the solvent was removed under reduced pressure. The residue was triturated with ether to give the product (1.3 g, 70%). ¹ H NMR (DMSO-d ₆ ) δ 6.91 (m, 1H), 6.89 (m, 1H), 6.72 (m, 1H), 6.01 (s, 2H), 3.53-3.41 (m, 1H), 3.07-2.89 (m, 4H).

Step 4 3- (1,3-Benzodioxol-5-yl) trifluoroacetic acid-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl ) -Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:
The title compound is prepared in the following general manner:

It was manufactured using.
100 mg of the above amide oxime (prepared according to the method as described in WO 99/30709) was added to an equal volume of the above anhydride suspended in dioxane (5 ml). The reaction mixture is heated to 95 ° C. overnight, the solvent is removed, and the residue is 10-50% acetonitrile gradient over 12 minutes for all compounds (but 5-12 minutes for pyridine and quinoline derivatives). Purified on HPLC (Gilson) with a 35% gradient). ¹ H NMR (DMSO-d ₆ ) δ 12.2 (br s, 1H), 8.13 (br s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 6.91-6.52 (m, 4H), 5.91 (s , 2H), 3.52-3.39 (m, 3H), 3.3-3.14 (m, 2H), 2.77-2.56 (m, 8H), 1.99-1.90 (m, 2H), 1.88-1.76 (m, 2H). 1.2 Analysis result of C ₂₄ H ₂₆ N ₄ O ₅ with CF ₃ CO ₂ H and 1.0 H ₂ O added: (calculated value) C, 52.38; H, 4.86; N, 9.26. (Actual value) C, 52.47; H , 4.47; N, 9.27.

  3- (3,4-Dichlorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 trifluoroacetic acid -Oxadiazol-5-yl} butanoic acid:

The title compound was prepared according to the method described for preparing the product of Example 1 using 3,4-dichlorophenylbenzaldehyde. ¹ H NMR (CD ₃ OD) δ 7.55 (d, 1 H), 7.50-7.40 (m, 2 H), 7.30-7.20 (m, 1 H), 6.55 (d, 1 H), 3.75-3.65 (m , 1 H), 3.50-3.45 (m, 2 H), 3.40-3.23 (m, 2 H), 2.90-2.60 (m, 8 H), 2.10-2.00 (m, 2 H), 2.00-1.90 (m , 2 H). Mass spectrum of C ₂₃ H ₂₄ Cl ₂ N ₄ O ₃ (ESI +) m / z 476.1 (M + H) ⁺ .

  Hydrochloric acid 3- (3-fluoro-4-methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid:

The title compound was prepared according to the procedure described for preparing the product of Example 1 using 3-fluoro-4-methylbenzaldehyde. ¹ H NMR (CDCl ₃ ) δ 8.45 (broad s, 1 H), 7.35 (d, 1 H), 7.15-7.10 (m, 1 H), 6.95-6.85 (m, 2 H), 6.40 (d, 1 H), 3.80-3.70 (m, 1 H), 3.55-3.47 (m, 2 H), 3.20-3.15 (m, 2 H), 2.9-2.7 (m, 8 H), 2.3-2.2 (m, 2 H), 2.23 (s, 3 H), 2.0-1.9 (m, 2H). Mass spectrum of C ₂₄ H ₂₇ FN ₄ O ₃ (ESI +) m / z 439.19 (M + H) ⁺ .

  3- (4-Phenoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid

The title compound was prepared using 4-phenoxybenzaldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (CD ₃ OD) δ 7.51 (d, 1 H), 7.35-7.28 (m, 2 H), 7.23 (d, 2 H), 7.13-7.05 (m, 1 H), 6.93-6.83 (m , 4 H), 6.34 (d, 1 H), 3.76-3.66 (m, 1 H), 3.52-3.45 (m, 2 H), 3.40-3.30 (m, 1 H), 3.29-3.20 (m, 1 H), 2.90-2.63 (m, 8 H), 2.10-2.00 (m, 2 H), 1.96-1.88 (m, 2 H); C ₂₉ H ₃₀ N ₄ O ₄ mass spectrum (ESI +) m / z 499.23 (M + H) ⁺ .

  3- (1-Benzofuran-2-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetate , 4-Oxadiazol-5-yl} butanoic acid

The title compound was prepared using benzofuran-2-aldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (CD ₃ OD) δ 7.50-7.44 (m, 2 H), 7.39 (d, 1 H), 7.23-7.13 (m, 2 H), 6.55 (s, 1 H), 6.48 (d, 1 H), 4.13-3.93 (m, 1 H), 3.50-3.40 (m, 2 H), 2.96-2.83 (m, 2 H), 2.80-2.76 (m, 2 H), 2.75-2.70 (m, 2 H), 2.66-2.60 (m, 2 H), 2.06-1.98 (m, 2 H), 1.98-1.90 (m, 2 H). Mass spectrum of C ₂₅ H ₂₆ N ₄ O ₄ (ESI +) m / z 447.14 (M + H) ⁺ .

  3- [4- (Benzyloxy) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetic acid , 4-Oxadiazol-5-yl} butanoic acid

The title compound was prepared using 4-benzyloxybenzaldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (CD ₃ OD) δ 7.56-7.53 (d, 1 H), 7.48-7.34 (m, 5 H), 7.23 (d, 2 H), 6.94 (d, 2 H), 6.55 (d, 1 H), 5.50-5.30 (s, 2 H), 3.78-3.68 (m, 1 H), 3.56-3.49 (m, 2 H), 3.44-3.35 (m, 1 H), 3.33-3.25 (m, 1 H), 2.93-2.84 (m, 1 H), 2.83-2.73 (m, 5 H), 2.70-2.63 (m, 2 H), 2.15-2.05 (m, 2 H), 2.00-1.93 (m, 2 H); Mass spectrum of C ₃₀ H ₃₂ N ₄ O ₄ (ESI +) m / z 513.88 (M + H) ⁺ .

  3- [4- (Methylsulfonyl) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetic acid , 4-Oxadiazol-5-yl} butanoic acid

The title compound was prepared using 4-methylsulfonylbenzaldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (CD ₃ OD) δ 7.85 (d, 2 H), 7.56 (d, 3 H), 6.55 (d, 1 H), 3.90-3.80 (m, 1 H), 3.54-3.50 (m, 2 H), 3.46-3.30 (m, 2 H), 3.09 (s, 3 H), 2.80-2.90 (m, 1 H), 2.86-2.80 (m, 3 H), 2.75-2.69 (m, 2 H) , 2.69-2.63 (m, 2 H), 2.06-1.93 (m, 4 H); Mass spectrum (ESI +) m / z 485.12 (M + H) ^{+ of} C ₂₄ H ₂₈ N ₄ O ₅ S.

  Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3- [4- (Trifluoromethoxy) phenyl] butanoic acid

The title compound was prepared using 4-trifluoromethoxybenzaldehyde according to the method described for preparing the product of Example 1. 1H NMR (DMSO-d6) δ) 8.05 (broad s, 1 H), 7.59 (d, 1 H), 7.40 (d, 2 H), 7.25 (d, 2 H), 6.55 (d, 1 H), 3.65-3.55 (m, 1 H), 3.39-3.21 (m, 4 H), 2.85-2.60 (m, 8 H), 1.95-1.86 (m, 2 H), 1.85-1.78 (m, 2 H); Mass spectrum (ESI +) m / z 491.12 (M + H) ^{+ of} C ₂₄ H ₂₅ F ₃ N ₄ O ₄ .

  3- (3-Furyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxatriacetate Diazol-5-yl} butanoic acid

The title compound was prepared using 3-furaldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (DMSO-d ₆ ) δ 8.00 (broad s, 1 H), 7.56 (d, 1 H), 7.52 (s, 1 H), 7.41 (s, 1 H), 6.56 (d, 1 H) , 6.43 (s, 1 H), 3.55-3.45 (m, 1 H), 3.29-3.11 (m, 4 H), 2.75-2.53 (m, 8 H), 2.01-1.91 (m, 2 H), 1.85 -1.75 (m, 2 H); mass spectrum (ESI +) m / z 397.55 (M + H) ^{+ of} C ₂₁ H ₂₄ N ₄ O ₄ .

  Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3-thien-3-yl-butanoic acid

The title compound was prepared using 3-thiophenecarboxaldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (DMSO-d ₆ ) δ 8.13 (broad s, 1 H), 7.59 (d, 1 H), 7.44-7.40 (m, 1 H), 7.20 (m, 1 H), 7.05 (m, 1 H), 6.56 (d, 1 H), 3.74-3.65 (m, 1 H), 3.33-3.18 (m, 4 H), 2.78-2.60 (m, 8 H), 2.00-1.91 (m, 2 H) , 1.86-1.78 (m, 2 H); mass spectrum of C ₂₁ H ₂₄ N ₄ O ₃ S (ESI +) m / z 413.10 (M + H) ⁺ .

  Hydrochloric acid 3- (2,3-dihydro-1,4-benzodioxin-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl ) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid

The title compound was prepared using 3,4-dihydrobenzodioxinaldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (CDCl ₃ ) δ 7.25 (d, 1 H), 6.78-6.63 (m, 3 H), 6.31 (d, 1 H), 4.27 (s, 4 H), 3.65-3.58 (m, 1 H ), 3.42 (t, 2 H), 3.15-3.02 (m, 2 H), 2.80-2.60 (m, 8 H), 2.21-2.12 (m, 2 H), 1.90-1.83 (m, 2 H); Mass spectrum (ESI +) m / z 465.18 (M + H) ^{+ of} C ₂₅ H ₂₈ N ₄ O ₅ .

  Hydrochloric acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} -3- [3- (Trifluoromethoxy) phenyl] butanoic acid

The title compound was prepared using 3-trifluoromethoxybenzaldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (CDCl ₃ ) δ 7.34-7.24 (m, 2 H), 7.20-7.00 (m, 3 H), 6.33 (d, 1 H), 3.81-3.71 (m, 1 H), 3.46-3.39 ( m, 2 H), 3.21-3.10 (m, 2 H), 2.89-2.60 (m, 8 H), 2.21-2.10 (m, 2 H), 1.92-1.83 (m, 2 H); C ₂₄ H ₂₅ Mass spectrum of F ₃ N ₄ O ₄ (ESI +) m / z 491.15 (M + H) ⁺ .

  Hydrochloric acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} -3- (3,4,5-trifluorophenyl) butanoic acid

The title compound was prepared using 3,4,5-trifluorobenzaldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (CDCl ₃ ) δ 8.38 (broad s, 1 H), 7.36 (d, 1 H), 6.93-6.88 (m, 2 H), 6.40 (d, 1 H), 3.80-3.71 (m, 1 H), 3.53-3.46 (m, 2 H), 3.20-3.15 (m, 2 H), 2.95-2.71 (m, 8 H), 2.29-2.20 (m, 2 H), 2.00-1.90 (m, 2 H); mass spectra of _{C 23 H 23 F 3 N 4} O 3 (ESI +) m / z 461.15 (M + H) +.

  Hydrochloric acid 3- (2,2-difluoro-1,3-benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid

The title compound was prepared using 2,2-difluoro-1,3-benzodiol-5-aldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (CDCl ₃ ) δ 8.49 (broad s, 1 H), 7.40 (d, 1 H), 7.08-7.00 (m, 3 H), 6.45 (d, 1 H), 3.90-3.81 (m, 1 H), 3.58-3.51 (m, 2 H), 3.28-3.21 (m, 2 H), 3.00-2.78 (m, 8 H), 2.33-2.25 (m, 2 H), 2.04-1.96 (m, 2 H); Mass spectrum of C ₂₄ H ₂₄ F ₂ N ₄ O ₅ (ESI +) m / z 486.90 (M + H) ⁺ .

  Hydrochloric acid 3- [3-fluoro-5- (trifluoromethyl) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl]- 1,2,4-oxadiazol-5-yl} butanoic acid

The title compound was prepared using 3-fluoro-5-trifluoromethyl-benzaldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (CDCl ₃ ) δ 8.62 (broad s, 1 H), 7.58 (d, 1 H), 7.55 (s, 1 H), 7.45-7.39 (m, 2 H), 6.63 (d, 1 H) , 4.15-4.06 (m, 1 H), 3.75-3.69 (m, 2 H), 3.48-3.41 (m, 2 H), 3.23-3.14 (m, 1 H), 3.03-2.95 (m, 8 H) , 2.50-2.41 (m, 2 H), 2.20-2.13 (m, 2 H); mass spectrum (ESI +) m / z 493.13 (M + H) ^{+ of} C ₂₄ H ₂₄ F ₄ N ₄ O ₃ .

  3- (6-methoxy-2-naphthyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 hydrochloride -Oxadiazol-5-yl} butanoic acid

The title compound was prepared using 6-methoxy-2-naphthuraldehyde according to the method described for preparing the product of Example 1. ¹ H NMR (CDCl ₃ ) δ 7.65-7.59 (m, 3 H), 7.61 ((7.29-7.21 (M, 2 H), 7.09-7.01 (M, 2 H), 6.04 (d, 1 H), 3.84) (s, 3 H), 3.45-3.39 (m, 2 H), 3.25-3.20 (d, 2 H), 2.95-2.86 (m, 1 H), 2.83-2.64 (m, 8 H), 2.20-2.10 (m, 2 H), 1.90-1.83 (m, 2 H); Mass spectrum of C ₂₈ H ₃₀ N ₄ O ₄ (ESI +) m / z 487.30 (M + H) ⁺ .

  3- (6-Methoxypyridin-3-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 -Oxadiazol-5-yl} butanoic acid

Reaction scheme 2:

  Step 1. Synthesis of dimethyl 3- (6-methoxypyridin-3-yl) pent-2-enedicarboxylate

Dimethylpent-2-enedicarboxylate (2.86 g, 18.09 mmol), palladium (II) acetate (0.12 g, 0.53 mmol), tri-o- in DMF (2.13 mL). A mixture of triphosphine (0.405 g, 1.33 mmol) and triethylamine (2.0 mL) was degassed and heated to 90 ° C. To this mixture, 5-bromo-2-methoxypyridine (1) was added dropwise and heated at 90 ° C. overnight. The reaction mixture was cooled to room temperature and the solid was filtered. The filtrate was diluted with water and the mixture was extracted with ethyl acetate (100 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography with 5-25% ethyl acetate / hexane to give dimethyl 3- (6-methoxypyridin-3-yl) pent-2-enedicarboxylate as a pale yellow oil. (0.301 g, 21%) was obtained. ¹ H NMR (CD ₃ OD) δ 8.31 (d, 1 H), 7.88-7.84 (m, 1 H), 6.84 (d, 1 H), 6.33 (s, 1 H), 4.86 (s, 2 H) , 3.95 (s, 3 H), 3.75 (s, 3 H), 3.68 (s, 3 H).

  Step 2. Synthesis of dimethyl 3- (6-methoxypyridin-3-yl) pentanedicarboxylate

Dimethyl 3- (6-methoxypyridin-3-yl) pent-2-enedicarboxylate (0.301 g, 1.13 mmol) in methanol and palladium on carbon (4%) were added to a standard bottle. ). Hydrogenation was carried out at room temperature and 5 psi for 2 hours. Mass spectrum of C ₁₃ H ₁₇ NO ₅ (ESI +) m / z 268.40 (M + H) ⁺ .

  Step 3. Synthesis of 3- (6-methoxypyridin-3-yl) pentanedioic acid

Dimethyl 3- (6-methoxypyridin-3-yl) pentanedicarboxylate (0.276 g, 1.034 mmol) in THF (17.20 mL) was added to water (17.20 mL) and KOH (0. 58 g) was added. The reaction mixture was stirred at room temperature overnight. Then concentrated hydrochloric acid was added until pH 2.0. During the addition, the temperature was kept below 50 ° C. The mixture was extracted with ethyl acetate (50 ml, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated to give 3- (6-methoxypyridin-3-yl) pentanedioic acid (0.145 g, 59%) as a white solid. Obtained. ¹ H NMR (CD ₃ OD) δ 8.05 (d, 1 H), 7.69-7.65 (m, 1 H), 6.78 (d, 1 H), 3.89 (s, 3 H), 3.60-3.51 (m, 1 H), 2.80-2.73 (m, 2 H), 2.65-2.58 (m, 2 H); Mass spectrum of C ₁₁ H ₁₃ NO ₅ (ESI +) m / z 240.30 (M + H) ⁺ .

  Step 4. Synthesis of 4- (6-methoxypyridin-3-yl) dihydropyran-2,6 (3H) -dione

  To 3- (6-methoxypyridin-3-yl) pentanedioic acid (0.276 g, 1.15 mmol) was added acetic anhydride (10.0 mL). The reaction mixture was stirred and heated at 100 ° C. for 5 hours. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure to give a dark brown solid, 4- (6-methoxypyridin-3-yl) dihydropyran-2,6 (3H) -dione (0.086 g, 34%). The sample was diluted with acetonitrile, 50 μL of piperidine was added, and liquid chromatography / mass spectrometry (LCMS) was performed. According to LCMS, the mass of the product was 307.40 m / z (M + piperidine).

  Step 5. 3- (6-Methoxypyridin-3-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, Synthesis of 2,4-oxadiazol-5-yl} butanoic acid

The above compound was prepared analogously to Example 1, Step 4, starting from 4- (6-methoxypyridin-3-yl) dihydropyran-2,6 (3H) -dione. Yield (0.038 g, 22%). ¹ H NMR (CD ₃ OD) δ 8.09 (d, 1 H), 7.04-7.69 (m, 1 H), 7.45 (d, 1 H), 6.80 (d, 1 H), 6.55 (d, 1 H) , 3.89 (s, 3 H), 3.79-3.70 (m, 1 H), 3.46-3.41 (m, 2 H), 3.21-3.18 (m, 2 H), 2.71-2.55 (m, 8 H), 2.19 -2.05 (m, 2 H), 1.98-1.89 (m, 2 H). Mass spectrum (ESI +) m / z 438.20 (M + H) ^{+ of} C ₂₃ H ₂₇ N ₅ O ₄ .

  3- (4-Cyanophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid

Step 1. Diethyl 3- (4-cyanophenyl) pentanedioate Diethyl 3- (4-bromophenyl) pentanedioate (1.0 g, 2.91 mmol) prepared as in Step 1 of Example 1 in degassed DMF Samples of water, zinc cyanide (0.212 g, 1.806 mmol), tris (dibenzylideacetone) dipalladium (0) (0.133 g, 0.145 mmol) and bis (diphenylphosphino) ferrocene (0 333 g, 0.601 mmol) was added. The reaction mixture was heated at 120 ° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate (50 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash master chromatography with 0-10% ethyl acetate / hexanes to give a pale green oil (0.280 g, 33%). ¹ H NMR (CD ₃ OD) δ 7.69 (d, 2 H), 7.50 (d, 2 H), 4.06-4.00 (m, 4 H), 3.72-3.63 (m, 1 H), 2.85-2.78 (m , 2 H), 2.75-2.65 (m, 2 H), 1.14 (t, 6 H).

Step 2. 3- (4-Cyanophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4- Oxadiazol-5-yl} butanoic acid The compound was prepared according to the method described for preparing the product of Example 1, starting from diethyl 3- (4-cyanophenyl) pentanedioate. ¹ H NMR (DMSO-d ₆ ) δ 7.72 (d, 2 H), 7.50 (d, 2 H), 7.02 (d, 1 H), 6.39 (broad s, 1 H), 6.20 (d, 1 H) , 3.69-3.60 (m, 1 H), 3.40-3.28 (m, 2 H), 3.26-3.20 (m, 2 H), 2.85-2.78 (m, 1 H), 2.71-2.62 (m, 1 H) , 2.62-2.51 (m, 4 H), 2.42-2.33 (m, 2 H), 1.91-1.83 (m, 2 H), 1.79-1.70 (m, 2 H); C ₂₄ H ₂₅ N ₅ O ₃ Mass spectrum (ESI +) m / z 432.60 (M + H) ⁺ .

  3- (3-Cyanophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid

The title compound was prepared following the same procedure as described for preparing the product of Example 18, starting from the corresponding bromo compound. ¹ H NMR (DMSO-d ₆ ) δ 7.82 (s, 1 H), 7.68-7.60 (m, 2 H), 7.50-7.45 (m, 1 H), 7.06 (d, 1 H), 6.42 (broad s , 1 H), 6.22 (d, 1 H), 3.68-3.58 (m, 1 H), 3.40-3.28 (m, 2 H), 3.28-3.20 (m, 2 H), 2.87-2.79 (m, 1 H), 2.75-2.65 (m, 1 H), 2.65-2.53 (m, 4 H), 2.40 (t, 2 H), 1.92-1.83 (m, 2 H), 1.79-1.71 (m, 2 H) ; Mass spectrum of C ₂₄ H ₂₅ N ₅ O ₃ (ESI +) m / z 432.20 (M + H) ⁺ .

3-Benzyl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole-5 trifluoroacetate -Ile} butanoic acid production
Reaction scheme 3 :

  Step 1.4-Benzyldihydro-2H-pyran-2,6 (3H) -dione:

  Starting from ethyl 4-phenylbut-2-enoate prepared according to the document "Legters, J .; Thijs, L .; Zwanenburg, B .; Recl. Trav. Chem. Pays-Bas 111; 1; 1992; 1-15" , Tokoroyama, Takashi; Kusaka, Hisahsi; Can. J. Chem .; 74; 12: 1996; 2487-2502 and Victory, Pedro; Alvarez-Larena, Angel; Barbera, Eduardo; Batllori. Xanvier; Borrell, Jose I .; Cordoba, Carlos; J. Chem. Res. Miniprint; 4; 1989, 0631-0674 ", 4-benzyldihydro-2H-pyran-2,6 (3H) -dione Was synthesized.

  Step 2. 3-Benzyl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole-5 trifluoroacetate -Il} butanoic acid

  3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (5-, 6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl trifluoroacetate 4-benzyldihydro-2H-pyran-2,6 as an anhydride according to the method described for preparing 1,2,4-oxadiazol-5-yl} butanoic acid (step 4 of Example 1) -(3H) -dione (3- (1,3-benzodioxol-5-yl) trifluoroacetate-4- {3- [3- (5,6,7,8-tetrahydro-1,8- Naphthyridin-2-yl) -propyl] -1,2,4-oxadiazol-5-yl} butanoic acid (prepared according to steps 1 to 3 in Example 1) Using 3-benzyl-4- {3- [3- (5 6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] was prepared 2,4-oxadiazol-5-yl} butanoic acid.

¹ H NMR (400MHz) DMSO-d ₆ δ 8.04 (br s, 1H), 7.66 (d, 1H), 7.22 (m, 5H), 6.61 (d, 1H), 3.40 (m, 3H), 2.88 (m , 2H), 2.72-2.55 (m, 8H), 2.27 (d, 2H), 1.99 (m, 2H), 1.81 (m, 2H) Mass spectrum: (MH ⁺ ) = 421.3.

3- (4-Fluoro-3-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, trifluoroacetic acid, 2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 4 :

Trifluoroacetic acid 3- (1,3-benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)- Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid according to the method described (Example 1, Step 4) and the appropriate anhydride (3- (1,3-trifluoroacetic acid). 3-Benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) -propyl] -1,2,4 Using the general method outlined for obtaining -oxadiazol-5-yl} butanoic acid (prepared according to example 1, steps 1-3), trifluoroacetic acid 3- (4-fluoro-3- Methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro- Was prepared 8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid. ¹ H NMR (400 MHZ) DMSO-d ₆ δ 7.81 (br s, 1H), 7.59 (d, 1H), 7.08-7.02 (m, 2H), 6.82-6.75 (m, 1H), 6.55 (d, 1H ), 3.78 (s, 3H), 3.6-3.2 (m, 5H), 2.8-2.6 (m, 8H), 1.99-1.91 (m, 2H), 1.89-1.79 (m, 2H) Mass spectrum: (MH ⁺ ) = 455.2.

Hydrochloric acid 3- (3-fluoro-5-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid
Reaction scheme 5:

  Step 1.1-Bromo-3-fluoro-5-methoxybenzene

1-Bromo-3,5-difluorobenzene (20 g, 103.63 mmol) was dissolved in N, N-dimethylformamide (50 mL) under nitrogen and the solution was cooled to 0.5 ° C. Then, sodium methoxide was gradually added so that the temperature did not exceed 5 ° C. The mixture was kept stirring at room temperature for 60 minutes. The reaction mixture was diluted with methylene chloride (50 mL). The solution was washed with water (50 mL, 2 times), then dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give the product 1-bromo-3-fluoro-5-methoxybenzene (6.34 g, 30%). ¹ H NMR (400 MHz) CDCl ₃ δ 7.09-7.06 (m, 1H), 6.86-6.76 (m, 1H), 6.58-6.54 (m, 1H), 3.81 (trip, 3H).

  Step 2. Ethyl (2E) -3- (3-fluoro-5-methoxyphenyl) prop-2-enoate

1-bromo-3-fluoro-5-methoxybenzene (2 g, 9.75 mmol), ethyl acrylate (1.32 mL, 12.19 mmol), palladium acetate (0.109 g, 0.49 mmol), sodium acetate (4 g, 48.75 mmol) and N, N-dimethylformamide (10 mL) were placed in a small vial and kept stirring at 100 ° C. for 16 hours. This was passed through a column of silica using 50 g of silica and a hexane / ethyl acetate (9: 1) solution as the eluent. The product was still impure and was once again run on a column of silica using 50 g of silica and a methylene chloride / ethyl acetate (9: 1) solution as the eluent. The clear fractions were collected and concentrated to give the product ethyl (2E) -3- (3-fluoro-5-methoxyphenyl) prop-2-enoate (2 g, ie 91%). ¹ H NMR (400MHz) CDCl ₃ δ 7.59-7.51 (d, 1H), 6.85-6.82 (m, 2H), 6.66-6.61 (m, 1H), 6.42-6.38 (d, 1H), 4.30-4.23 (quar , 2H), 3.82 (s, 3H), 1.37-1.32 (trip, 3H).

  Step 3.4- (3-Fluoro-5-methoxyphenyl) dihydro-2H-pyran-2,6 (3H) -dione

  References Tokoroyama, Takashi; Kusaka, Hisashi; Can. J. Chem .; 74; 12; 1996; 2487-2502 and Victory, Pedro; Alvarez-Larena, Angel; Barbera, Eduardo; Batllori. Xavier; Borrell, Jose I .; Cordoba, Carlos; J. Chem. Res. Miniprint; 4; 1989; 0631-0674 ”from the product of Step 2 to 4- (3-fluoro-5-methoxyphenyl) dihydro- 2H-pyran-2,6 (3H) -dione was synthesized.

  Step 4. Hydrochloric acid 3- (3-fluoro-5-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid

Trifluoroacetic acid 3- (1,3-benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)- Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid according to the same method as described for the preparation of Example 1 (step 4), 3- (3-fluoro-5-methoxy hydrochloride) Phenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} butane The acid was produced. ¹ H NMR (DMSO-d ₆ ) δ 7.75 (br s, 1H), 7.58 (d, 1H), 6.72-6.65 (m, 2H), 6.64-6.62 (m, 1H), 6.54 (d, 1H), 3.71 (s, 3H), 3.6-3.2 (m, 5H), 2.8-2.6 (m, 8H), 1.99-1.91 (m, 2H), 1.89-1.79 (m, 2H) Mass spectrum: (MH ⁺ ) = 455.2.

3- (2-Methyl-1,3-benzothiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl hydrochloride ] -1,2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 6:

Using commercially available 5-bromo-2-methylbenzothiazole, hydrochloric acid 3- (3-fluoro-5-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1, 8-Naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid according to the method described in the preparation of 3- (2-methyl-1,3-benzothiazole-hydrochloride 5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl } Butanoic acid was produced. ¹ H NMR (400MHZ) DMSO-d ₆ δ 7.89-7.87 (d, 1H), 7.78-7.73 (m, 2H), 7.60-7.58 (d, 1H), 7.31-7.29 (m, 1H), 6.52-6.50 (d, 1H), 3.73-3.66 (m, 1H), 3.41-3.30 (m, 4H), 2.89-2.57 (m, 11H), 1.93-1.79 (m, 4H) Mass spectrum: (MH ⁺ ) = 520 .

Hydrochloric acid 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 7:

  Step 1.2- (4-Chlorophenyl) -1,3-thiazole-5-carbaldehyde

4-Chlorobenzene-1-carbothioamide (5 g, 29.1 mmol), magnesium hydroxide carbonate pentahydrate (7.06 g, 14.55 mmol) and 2-chloromalonaldehyde (4.65 g, 43.65 mmol) (literature) “Comforth, Fawaz, Goldsworthy and Robinson; J. Chem. Soc. 1949, 1550”) was placed in a flask and stirred at 60 ° C. for 3 hours under nitrogen. The reaction mixture was then passed through a plug of silica and washed with ethyl acetate. The solvent was removed in vacuo to give the product 2- (4-chlorophenyl) -1,3-thiazole-5-carbaldehyde (6 g, 92%). ¹ H NMR (400 MHz) CDCl ₃ δ 10.06 (s, 1H), 8.43 (s, 1H), 7.99-7.96 (m, 2H), 7.49-7.46 (2H).

  Step 2.4 4- [2- (4-Chlorophenyl) -1,3-thiazol-5-yl] dihydro-2H-pyran-2,6 (3H) -dione

  3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (5-, 6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl trifluoroacetate According to the general procedure outlined for obtaining 1,2,4-oxadiazol-5-yl} butanoic acid (Example 1, steps 1-3), 4- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] dihydro-2H-pyran-2,6 (3H) -dione was prepared.

  Step 3. Hydrochloric acid 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (5-, 6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl trifluoroacetate In accordance with a method similar to that described for preparing 1,2,4-oxadiazol-5-yl} butanoic acid (Example 1, Step 4), 3- [2- (4-chlorophenyl) hydrochloride -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4- Oxadiazol-5-yl} butanoic acid was prepared. ¹ H NMR (400mHz) DMSO-d ₆ δ 7.85-7.82 (m, 2H), 7.78 (br s, 1H), 7.70 (s, 1H), 7.54-7.51 (m, 3H), 6.50 (d, 1H) , 3.44-3.40 (m, 5H), 2.9-2.6 (m, 8H), 1.96-1.91 (m, 2H), 1.81 (m, 2H), mass spectrum: (MH ⁺ ) = 525.

3- [2- (4-Methoxyphenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 hydrochloride -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 8

Hydrochloric acid 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid according to the method described for the preparation of 3- [2- (4-methoxyphenyl) hydrochloride starting from the appropriate thioamide -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4- Oxadiazol-5-yl} butanoic acid was prepared. ¹ H NMR (400MHz) DMSO-d ₆ δ 13.78 (br s, 1H), 7.88 (br s, 1H), 7.76-7.75 (m, 2H), 7.60 (s, 1H), 7.53 (d, 1H), 7.02-6.99 (m, 2H), 6.53-6.51 (d, 1H), 3.99-3.86 9m, 1H), 3.83 (s, 3H), 3.46-3.29 (m, 4H), 2.93-2.62 (m, 8H) , 2.01-1.91 (m, 2H), 1.84-1.76 (m, 2H). Mass spectrum: (MH ⁺ ) = 520.

3- (2-Methyl-1,3-benzothiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl hydrochloride ] -1,2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 9

Hydrochloric acid 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid, starting from the appropriate thioamide according to the method described for the preparation of 3- (2-methyl-1,3-hydrochloric acid Benzothiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole- 5-yl} butanoic acid was prepared. ¹ H NMR (400MHz) DMSO-d ₆ δ 7.77-7.75 (m, 3H), 7.63-7.61 (m, 2H), 7.42-7.39 (m, 3H), 6.42-6.37 (d, 1H), 3.95-3.88 (m, 1H), 3.34-3.28 (m, 4H), 2.89-2.53 (m, 8H), 1.94-1.87 (m, 2H), 1.76-1.70 (m, 2H) Mass spectrum: (MH ⁺ ) = 490.6 .

Hydrochloric acid 3- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 10

  Step 1.3-Fluorobenzenecarbothioamide

3-Fluorobenzonitrile (10 g, 82.6 mmol), triethylamine (6 mL) and pyridine (60 mL) were charged to the flask and hydrogen sulfide gas was bubbled through the reaction mixture for 5 minutes. The reaction flask was then capped and left for 48 hours. The solvent was subsequently dried with nitrogen and left under vacuum to give the product (12.00 g, 94%). ^{1 H NMR (400MHz) DMSO-} d 6 δ 10.05 (s, 1H), 9.60 (s, 1H), 7.72-7.71 (m, 2H), 7.48-7.32 (m, 2H).

  Step 2-6. Hydrochloric acid 3- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

Hydrochloric acid 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid according to the method described for the preparation of 3-fluorobenzenecarbothioamide with 3- [2- (4-fluorophenyl) hydrochloride -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4- Conversion to oxadiazol-5-yl} butanoic acid. ¹ H NMR (400MHz) DMSO-d ₆ δ 7.87 (br s, 1H), 7.7 (s, 1H), 7.65-7.47 (m, 3H), 7.33-7.28 (m, 2H), 6.53-6.51 (d, 1H), 4.05-3.95 (m, 1H), 3.56-3.34 (m, 4H), 2.96-2.63 (m, 8H), 2.00-1.93 (m, 2H), 1.83-1.80 (m, 2H). Mass spectrum : (MH ⁺ ) = 508.1.

3- [2- (3,5-Difluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine hydrochloride -2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 11

Hydrochloric acid 3- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid according to the method described for the preparation of 3- [2- (3,5 hydrochloric acid starting from the appropriate benzonitrile -Difluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, 2,4-oxadiazol-5-yl} butanoic acid was prepared. ¹ H NMR (400MHz) DMSO-d ₆ δ 7.95 (br s, 1H), 7.77 (s, 1H), 7.54-7.51 (m, 3H), 7.40-7.32 (m, 1H), 6.53-6.51 (d, 1H), 4.04-3.96 (m, 1H), 3.50-3.34 (m, 4H), 2.96-2.63 (m, 8H), 2.01-1.94 (m, 2H), 1.84-1.78 (m, 2H). Mass spectrum : (MH ⁺ ) = 526.2.

3- [2- (3,4-Difluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine hydrochloride -2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 12

Hydrochloric acid 3- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid, starting from the appropriate benzonitrile according to the method described for the preparation of 3- [2- (3,4 -Difluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, 2,4-oxadiazol-5-yl} butanoic acid was prepared. ¹ H NMR (400MHz) DMSO-d ₆ δ 7.88-7.83 (m, 2H), 7.71 (s, 1H), 7.69-7.66 (m, 1H), 7.59-7.50 (m, 2H), 6.53-6.52 (d , 1H), 3.99-3.95 (m, 1H), 3.49-3.30 (m, 4H), 2.95-2.63 (m, 8H), 2.01-1.94 (m, 2H), 1.84-1.78 (m, 2H). Spectrum: (MH ⁺ ) = 526.2.

Hydrochloric acid 3- [2- (2-furyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 13

Hydrochloric acid 3- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 3- [2- (2-Furyl) hydrochloride starting from the appropriate nitrile according to the method described for preparing -yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4- Oxadiazol-5-yl} butanoic acid was prepared. ¹ H NMR (400MHz) DMSO-d ₆ δ 7.87 (br s, 1H), 7.83 (m, 1H), 7.63 (s, 1H), 7.56 (d, 1H), 6.97 (m, 1H), 6.67-6.66 (m, 1H), 6.54 (d, 1H), 3.98-3.93 (m, 1H), 3.47-3.32 (m, 4H), 2.94-2.66 (m, 8H), 2.01-1.94 (m, 2H), 1.84 -1.78 (m, 2H). Mass spectrum: (MH ⁺ ) = 480.1.

  3- (3,4-Dimethoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid

The compounds in this example and the following examples (32 to 37) were synthesized in the same manner as in Example 1, starting from the corresponding substituted aryl aldehyde or substituted heteroaryl aldehyde. ¹ H NMR (DMSO-d ₆ ) δ 7.74 (br s, 1H), 7.6 (d, J = 7.5 Hz, 1H), 6.85-6.70 (m, 3H), 6.55 (d, J = 7.5 Hz, 1H) , 3.69 (s, 3H), 3.66 (s, 3H), 3.54-3.39 (m, 5H), 3.31- 3.16 (m, 2H), 2.73-2.60 (m, 6H), 1.99-1.89 (m, 2H) , 1.85-1.76 (m, 2H). Mass spectrum: (MH ⁺ ) = 467.

  3- (3,5-dimethoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid

¹ H NMR (DMSO-d ₆ ) δ 12.20 (br s, 1H), 7.91 (br s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6.39 (m, 2H), 6.30 (m, 1H), 3.69 (s, 6H), 3.54-3.39 (m, 5H), 3.31- 3.16 (m, 2H), 2.73-2.60 (m, 6H), 1.99- 1.89 (m, 2H), 1.85-1.76 (m, 2H). Mass spectrum: (MH ⁺ ) = 467.

  3- (3,5-dichlorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 trifluoroacetic acid -Oxadiazol-5-yl} butanoic acid

¹ H NMR (DMSO-d ₆ ) 12.3 (br s, 1H), 7.85 (br s, 1H), 7.6 (d, J = 7.5 Hz, 1H), 7.42-7.35 (m, 3H), 6.55 (d, J = 7.5 Hz, 1H), 3.62-3.5 (m, 2H), 3.4- 3.22 (m, 4H), 2.85-2.6 (m, 7H), 1.99-1.89 (m, 2H), 1.85-1.76 (m, 2H). Mass spectrum: (MH ⁺ ) = 476.

  3- (3,5-Difluorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid

¹ H NMR (DMSO-d ₆ ) δ 7.70 (br s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.09-7.0 (m, 3H), 6.50 (d, J = 7.5 Hz, 1H) , 3.62-3.53 (m, 1H), 3.4- 3.22 (m, 4H), 2.85-2.6 (m, 8H), 1.99-1.89 (m, 2H), 1.85-1.76 (m, 2H). Mass spectrum: ( MH ⁺ ) = 443.

  3- (3-Fluoro-4-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetic acid , 4-Oxadiazol-5-yl} butanoic acid

¹ H NMR (DMSO-d ₆ ) δ 12.20 (br s, 1H), 7.91 (br s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.25-7.20 (m, 2H), 7.1-7.0 (m, 2H), 6.60 (d, J = 7.5 Hz, 2H), 3.80 (s, 3H), 3.63-3.41 (m, 3H), 3.38- 3.21 (m, 2H), 2.82-2.63 (m, 6H ), 1.99-1.89 (m, 2H), 1.85-1.76 (m, 2H). Mass spectrum: (MH ⁺ ) = 455.

  Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3- [4- (Trifluoromethyl) phenyl] butanoic acid

¹ H NMR (DMSO-d ₆ ) δ 12.3 (br s, 1H), 7.72 (br s, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.5 Hz, 2H), 6.52 (d, J = 7.5 Hz, 1H), 3.70-3.60 (m, 1H), 3.4- 3.27 (m, 4H), 2.85-2.55 (m, 8H) , 1.99-1.89 (m, 2H), 1.85-1.76 (m, 2H). Mass spectrum: (MH ⁺ ) = 475.

  3- (2-Methyl-1,3-thiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) trifluoroacetate Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid

¹ H NMR (DMSO-d ₆ ) δ 12.45 (br s, 1H), 7.80 (br s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.34 (s, 1H), 6.58 (d, J = 7.5 Hz, 1H), 3.91-3.80 (m, 1H), 3.45- 3.22 (m, 4H), 2.90-2.64 (m, 8H), 2.53 (s, 3H), 2.01-1.92 (m, 2H), 1.85-1.76 (m, 2H). Mass spectrum: (MH ⁺ ) = 427.

  3- (1-Phenyl-1H-pyrazol-4-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] trifluoroacetate -1,2,4-oxadiazol-5-yl} butanoic acid

The above compounds were prepared according to the methods in Examples 32-37 according to 1-phenyl-1H-pyrazole-4-carbaldehyde (literature “Muri, Estela MF; Barreiro, Eliezer J .; Fraga, Carlos AM; Synth. Commun; 28; 7; 1998; 1299-1321 ”). ¹ H NMR (DMSO-d ₆ ) δ 12.3 (br s, 1H), 8.35 (s, 1H), 7.91 (br s, 1H), 7.73-7.70 (m, 2H), 7.59 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.44 (t, 2H), 7.25 (t, 1H), 6.52 (d, J = 7.5 Hz, 1H), 3.65-3.55 (m, 1H), 3.43- 3.20 ( m, 4H), 2.81-2.60 (m, 8H), 1.99-1.89 (m, 2H), 1.85-1.76 (m, 2H). Mass spectrum: (MH ⁺ ) = 473.

  3- (1-Benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 hydrochloride -Oxadiazol-5-yl} butanoic acid

Step 1. Triethyl 2- (1-benzofuran-6-yl) propane-1,1,3-tricarboxylate: sodium ethoxide (7.5 mL, 19.9 mmol), diethyl malonate (3 mL, 19.9 mmol) and ether ( 50 mL) was stirred for 30 minutes. Subsequently, 3- (benzofuran-6-yl) -acrylic acid ethyl ester (4.3 g, 19.9 mmol: prepared according to the method “International Patent Application WO 99/30709” by Duggan, Mark et al.) Is added and the reaction mixture is 5 Reflux for hours. The mixture was cooled to room temperature, acidified with aqueous acetic acid and extracted with ether. The ether was extracted with saturated bicarbonate solution, brine, dried (Na ₂ SO ₄ ) and concentrated to give 6.6 g of product (88%). The NMR spectrum of this product was consistent with the expected structure.

Step 2. Diethyl 3- (1-benzofuran-6-yl) pentanedioic acid: Triethyl 2- (1-benzofuran-6-yl) propane-1,1,3-tricarboxylate (6.6 g, 17.5 mmol) was added to DMSO (28 mL) and H ₂ O (0.28 mL) and NaCl (520 mg, 8.8 mmol) were added. The mixture was heated to 160 ° C. over 8 hours and then cooled to room temperature. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate and the ethyl acetate fraction was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash column chromatography (eluent, 20% ethyl acetate: 80% hexane) to give 4.4 g of product (83%). The NMR spectrum of the product was consistent with the expected structure.

Step 3.4 4- (1-Benzofuran-6-yl) dihydro-2H-pyran-2,6 (3H) -dione: Diethyl 3- (1-benzofuran-6-yl) pentanedioic acid (1.5 g, 4 0.9 mmol) was dissolved in a mixture of 15 mL of methanol and 15 mL of THF and 15 mL of 1N NaOH solution was added. The reaction mixture was stirred overnight at ambient temperature. The volatile solvent was removed and the remaining aqueous solution was acidified with 1N HCl to pH1. The aqueous solution was extracted with ethyl acetate (twice). The ethyl acetate fractions were combined, dried (Na ₂ SO ₄ ) and concentrated to give the desired product in quantitative yield. The NMR spectrum of the product was consistent with the expected structure. This product was converted to 4- (1-benzofuran-6-yl) dihydro-2H-pyran-2,6 (3H) -dione as shown in the previous examples.

Step 4. 3- (1-Benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 hydrochloride -Oxadiazol-5-yl} butanoic acid This compound was prepared using the method described in the previous examples starting from the product of Step 3. ¹ H NMR (DMSO-d ₆ ) δ 12.25 (br s, 1H), 8.02 (br s, 1H), 7.96-7.9 (m, 1H), 7.6-7.5 (m, 2H), 7.41-7.12 (m, 2H), 7.05-6.85 (m, 1H), 6.48-6.43 (m, 1H), 4.00-3.63 (m, 1H), 3.46-3.28 (m, 4H), 2.95-2.53 (m, 8H), 1.99- 1.90 (m, 2H), 1.88-1.76 (m, 2H). Mass Spectrum: (MH ⁺ ) = 449. Mass Spectrum: (MH ⁺ ) = 447.

  Hydrochloric acid 3- (2,3-dihydro-1-benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid

Diethyl 3- (1-benzofuran-6-yl) pentanedioate (2.63 g, 8.6 mmol) is dissolved in ethanol / water / acetic acid (52 mL / 6 mL / 2 mL) and the solution is degassed with argon. Treated with Pd (OH) ₂ (320 mg). The mixture was placed under 1 atm H ₂ and stirred at room temperature overnight. The mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated and purified by flash chromatography (10% ethyl acetate: 90% hexane) to give 2.35 g (96%) of the desired product. The title compound was synthesized using this product as in Example 1. ¹ H NMR (DMSO-d ₆ ) δ 12.2 (br s, 1H), 7.85 (br s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.5-6.8 (m, 2H), 6.79 (d , J = 7.5 Hz, 1H), 6.7-6.6 (m, 1H), 6.52 (t, 2H), 4.48-4.40 (m, 2H), 3.62-3.39 (m, 3H), 3.3-3.03 (m, 4H ), 2.80-2.60 (m, 6H), 1.99-1.90 (m, 2H), 1.88-1.76 (m, 2H). Mass spectrum: (MH ⁺ ) = 449.

  The following compounds were synthesized using the methods described in the series of previous examples.

  3- (1,3-Benzodioxol-5-yl) -4- (3- {3-[(pyridin-2-ylamino) methyl] phenyl} -1,2,4-oxadiazole-5 hydrochloride -Yl) butanoic acid

3- (1,3-Benzodioxol-5-yl) -4- (3- {3-[(pyridin-2-ylamino) methyl] phenyl} -1,2,4-oxadiazole-5 hydrochloride -Yl) butanoic acid. ¹ H NMR (DMSO-d ₆ ) δ 12.2 (br s, 1H), 9.06 (br s, 1H), 8.01-7.88 (m, 4H), 7.62-7.53 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 6.96 (m, 1H), 6.88 (t, 1H), 6.78-6.68 (m, 2H), 5.95 (s, 2H), 4.7 (m, 2H), 3.62-3.52 (m, 1H ), 3.42-3.25 (m, 2H), 2.71-2.59 (m, 2H). Mass spectrum: (MH ⁺ ) = 459.

3- (7-Fluoro-1,3-benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2) trifluoroacetic acid -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 14

Step 1.3-Fluoro-4,5-dihydroxybenzaldehyde:
According to the method of literature `` Kirk, K .; Cantacuzene, D .; Collins, B ,; Chen, G .; Nimit, Y .; Creveling. C .; J. Med. Chem. 1982, 25, 680-684 '' It was.

Step 2.7-Fluoro-1,3-benzodioxole-5-carbaldehyde:
The method of the literature “Zelle, R ,; McClellan, W .; Tetrahedron Letters, 1991, 32, 2461-2464” was followed. To a stirred suspension of 3-fluoro-4,5-dihydroxybenzaldehyde (087 g, 0.00561 mol) and Cs ₂ CO ₃ (2.74 g, 0.0842 mol) in anhydrous DMF (15 mL) was added BrCH ₂ Cl (0 .55 mL, 0.00842 mol) was added and the resulting mixture was heated at 110 ° C. for 2 hours. The reaction was cooled to 25 ° C. and filtered through a pad of celite with EtAOc flowing. The filtrate was concentrated and the residue was diluted with water and extracted with EtOAc. The extracts were combined, washed with water, brine, dried over anhydrous MgSO ₄ , filtered and concentrated to give 0.67 g (71%) of a tan solid.

Step 3.4- (7-Fluoro-1,3-benzodioxol-5-yl) dihydro-2H-pyran-2,6 (3H) -dione:
Starting from 7-fluoro-1,3-benzodioxol-5-carbaldehyde, the references "Tokoroyama, Takashi; Kusaka, Hisashi; Can. J. Chem .; 74; 12; 1996; 2487-2502", "Victory, P .; Alverez-Larena, A .; Barhera, E .; J. Chem. Res.Miniprint; 4; 1989; 0631-0674", "Hofman, S .; Baecke, GD; Kenda, B .; The above compounds were synthesized according to the method outlined in Clercq, PJ De Synthesis; 1998; 479-489.

Step 4. 3- (7-Fluoro-1,3-benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2) trifluoroacetic acid -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:
The title compound was prepared following a similar procedure as described for preparing the anhydride from Step 3. ¹ H NMR (CD ₃ OD) δ 7.52 (d, 1H), 6.61 (d, 1H), 6.57 (d, 1H), 6.53 (d, 1H), 5.91 (m, 2H), 3.60 (m, 1H) , 3.48 (m, 2H), 3.29 (m, 2H), 3.25 (m, 2H), 2.80 (m, 2H), 2.70 (m, 4H), 2.04 (m, 2H), 1.93 (m, 2H). Mass spectrum: (MH ⁺ ) = 469.20.

3- (1,3-Benzoxazol-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1 hydrochloride , 2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 15

The title compound was prepared according to the method outlined in Reaction Scheme 15 and using the methods described in a series of the previous examples. ¹ H NMR (CD ₃ OD) 8.21 (s, 1H), 7.83 (d, 1H), 7.58 (d, 1H), 6.75 (d, 1H), 6.67 (m, 1H), 6.52 (d, 1H), 3.61 (m, 1H), 3.50 (m, 2H), 3.30 (m, 2H), 2.75 (m, 2H), 2.64 (m, 2H), 2.60 (m, 2H), 2.05 (m, 2H), 1.95 (m, 2H). Mass spectrum: (MH ⁺ ) = 448.20.

3- (3-Methyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-trifluoroacetic acid 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid
Reaction scheme 16

  Step 1. Diethyl-3- (dimethoxymethyl) pentanedioate:

  Literatures `` Tokoroyama, Takashi; Kusaka, Hisashi; Can. J. Chem .; 74; 12; 1996; 2487-2502 '', Victory, P .; Alverez-Larena, A .; Barhera, E .; J. Chem. Res. Miniprint; 4; 1989; 0631-0674 ", Hofman, S .; Baecke, GD; Kenda, B .; The above compound was synthesized.

  Step 2. 4-Ethoxy-2- (2-ethoxy-2-oxoethyl) -4-oxobutanoic acid:

  Literature "Eillison, R., Lukenbach, E., Chiu, C.; Tetrahedron Letters; 1975, 8, 499-502" and "Bal, BS; Childers, WE Jr .; Pinnick, W. Tetrahedron 37, 1981, 2091 The above compound was synthesized from diethyl 3- (dimethoxymethyl) pentanedioate according to the method outlined in "-2096".

  Step 3. N'-hydroxyethaneimidamide:

  The above compounds were synthesized according to the method outlined in the literature “Bedford, C. D .; Miller, A .; J. Med. Chem .; 1986, 29, 2174-2183”.

  Step 4. Diethyl 3- (3-methyl-1,2,4-oxadiazol-5-yl) pentanedioate:

  By coupling N′-hydroxyethaneimidamide and 4-ethoxy-2- (2-ethoxy-2-oxoethyl) -4-oxobutanoic acid according to the method described in the series of previous examples, A compound was obtained.

  Step 5. 3- (3-Methyl-1,2,4-oxadiazol-5-yl) pentanedioic acid:

  The above compound was prepared from diethyl 3- (3-methyl-1,2,4-oxadiazol-5-yl) pentanedioate according to a method similar to that described for preparing the compound of Example 1 Step 2. Manufactured.

  Step 6. 4- (3-Methyl-1,2,4-oxadiazol-5-yl) dihydro-2H-pyran-2,6 (3H) -dione:

  Example 1 The above compound was prepared from 3- (3-methyl-1,2,4-oxadiazol-5-yl) pentanedioic acid according to a similar procedure as described for preparing the compound of Step 3. Manufactured.

  Step 7. 3- (3-Methyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-trifluoroacetic acid 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

EXAMPLE 1 Following a similar procedure as described for preparing the compound of step 4, the compound of step 6 “4- (3-methyl-1,2,4-oxadiazol-5-yl) dihydro- The title compound was prepared using the appropriate anhydride from 2H-pyran-2,6- (3H) -dione. ¹ H NMR (CDCl ₃ ) 9.45 (s, br, 1H), 7.38 (d, 1H), 6.43 (d, 1H), 5.30 (s, 1H), 4.08 (m, 1H), 3.50 (m, 2H) , 3.45 (m, 2H), 3.05 (m, 2H), 2.79 (m, 4H), 2.39 (s, 3H), 2.15 (m, 2H), 1.95 (m, 2H). Mass spectrum: (MH ⁺ ) = 413.2.

  3- (3-Ethyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-trifluoroacetic acid 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

  The compound of Example 44 “trifluoroacetic acid 3- (3-methyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid "according to a method similar to that described for producing (steps 1-7) 4 'N'-hydroxypropaneimidamide (reference "Bedford, CD; Howd, RA; Dailey, OD; Miller, A .; J. Med. Chem .; 1986, 29, 2174-2183") The title compound was prepared.

¹ H NMR (CD ₃ OD) 7.60 (d, 1H), 6.63 (d, 1H), 4.05 (m, 1H), 3.50 (m, 4H), 3.00 (m, 2H), 2.88 (m, 2H), 2.78 (m, 4H), 2.70 (m, 2H), 2.11 (m, 2H), 1.96 (d, 2H), 1.25 (m, 3H), mass spectrum: (MH ⁺ ) = 427.50.

  3- (3-Phenyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-trifluoroacetic acid 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

Example 45 Compound “Trifluoroacetic acid 3- (3-methyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid "according to a method similar to that described for producing (steps 1-7) The title compound was prepared using 4 N′-hydroxybenzimidamide. ¹ H NMR (CD ₃ OD) 7.98 (d, 2H), 7.50 (m, 4H), 6.52 (d, 1H), 4.25 (m, 1H), 3.58 (m, 2H), 3.50 (m, 2H), 3.08 (m, 2H), 2.80 (m, 4H), 2.65 (m, 2H), 2.05 (m, 2H), 1.95 (d, 2H), mass spectrum: (MH ⁺ ) = 475.60.

Examples 47-67
The compounds of Examples 47-67 are described in the literature "Vogel, AI; J. Chem. Soc .; 1934; pp 1758-1765", "McElvain, SM; Clemens, DH; J. Amer. Chem. Soc .; 80; 3915-3923 (1958) '', `` Diederich, F .; Dick, K .; Chem. Ber .; 118, 3817-3829 (1985) ''. And synthesized.

  Trifluoroacetic acid [1-benzoyl-4-({3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} methyl) piperidin-4-yl] acetic acid:

¹ H NMR (CD3OD) δ 1.70-1.96 (m, 4 H), 2.03 (m, 2 H), 2.21 (m, 2 H), 2.64 (s, 2 H), 2.88 (m, 6 H), 3.44 (s, 2 H), 3.58 (m, 4 H), 3.83 (m, 1 H), 3.98 (m, 1 H), 6.71 (d, 1 H), 7.48 (m, 2 H), 7.55 (m , 3 H), 7.65 (m, 1 H); Mass spectrum (ESI +) m / z 504.7 (M + H) + of C28H33N5O4.

  Trifluoroacetic acid [1-benzoyl-4-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) piperidin-4-yl] acetic acid

¹ H NMR (CD ₃ OD) δ 1.61-1.96 (m, 10 H), 2.57 (s, 2 H), 2.84 (t, 2 H), 3.38 (s, 2 H), 3.42 (t, 2 H) , 3.51 (m, 1 H), 3.78 (m, 1 H), 3.90 (m, 1 H), 6.89 (m, 1 H), 7.05 (m, 1 H), 7.42 (m, 2 H), 7.48 (m, 3 H), 7.81 (m, 1 H), 7.89 (m, 1 H); Mass spectrum of C26H31N5O4 (ESI +) m / z 478.2466 (M + H) +.

  Trifluoroacetic acid [1- (tert-butoxycarbonyl) -4-({3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} methyl) piperidin-4-yl] acetic acid

¹ H NMR (CD ₃ OD) δ 1.47 (s, 9 H), 1.57-1.73 (m, 3 H), 1.98 (m, 3 H), 2.14 (m, 2 H), 2.50-2.69 (m, 3 H), 2.83 (m, 6 H), 3.27 (s, 2 H), 3.40-3.62 (m, 4 H), 6.64 (d, 1 H), 7.60 (d, 1 H); mass spectrum of C26H37N5O5 ( ESI +) m / z 500.7 (M + H) +.

  Trifluoroacetic acid [1- (tert-butoxycarbonyl) -4-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) piperidine- 4-yl] acetic acid:

¹ H NMR (CD ₃ OD) δ 1.48 (s, 9 H), 1.5-2.0 (m, 7 H), 2.46-2.62 (m, 2 H), 2.82 (t, 2 H), 3.25 (s, 2 H), 3.38 (s, 2 H), 3.39-3.6 (m, 4 H), 6.83 (m, 1 H), 6.98 (m, 1 H), 7.84 (m, 2 H); mass spectrum of C24H35N5O5 ( ESI +) m / z 474.2736 (M + H) +.

  3- (4-Methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.97 (m, 2 H), 2.08 (m, 2 H), 2.26 (s, 3 H), 2.65-2.86 (m, 8 H), 3.20-3.38 (m, 2 H), 3.51 (m, 2 H), 3.68 (m, 1 H), 6.58 (d, 1 H), 7.07-7.18 (m, 4 H), 7.57 (d, 1 H); mass spectrum of C24H28N4O3 ( ESI +) m / z 421 (M + H) +.

  3- (3-Chlorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole hydrochloride -5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.98 (m, 2 H), 2.08 (m, 2 H), 2.60-2.90 (m, 8 H), 3.25-3.40 (m, 2 H), 3.51 (m, 2 H), 3.72 (m, 1 H), 6.58 (d, 1 H), 7.19-7.32 (m, 4 H), 7.57 (d, 1 H); Mass spectrum of C23H25ClN4O3 (ESI +) m / z 441 (M + H) +.

  Hydrochloric acid 3- (4-methoxy-3-methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.98 (m, 2 H), 2.07 (m, 2 H), 2.13 (s, 3 H), 2.64-2.85 (m, 8 H), 3.19-3.35 (m, 2 H), 3.52 (m, 2 H), 3.62 (m, 1 H), 3.77 (s, 3 H), 6.56 (d, 1 H), 6.78 (d, 1 H), 7.00-7.10 (m, 2 H), 7.58 (d, 1 H); Mass spectrum (ESI +) m / z 451 (M + H) + of C25H30N4O4.

  3- [4- (Methylthio) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.95 (m, 2 H), 2.06 (m, 2 H), 2.42 (s, 3 H), 2.62-2.88 (m, 8 H), 3.22-3.38 (m, 2 H), 3.52 (m, 2 H), 3.68 (m, 1 H), 6.55 (d, 1 H), 7.17 (m, 4 H), 7.58 (d, 1 H); Mass spectrum of C24H28N4O3S (ESI +) m / z 453 (M + H) +.

  3- (1-Methyl-1H-indol-3-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] trifluoroacetate -1,2,4-oxadiazol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.97 (m, 4 H), 2.55 (m, 2 H), 2.68 (m, 2 H), 2.80 (m, 2 H), 2.90 (m, 2 H), 3.35 -3.46 (m, 2 H), 3.50 (m, 2 H), 3.72 (m, 3 H), 4.05 (m, 1 H), 6.43 (d, 1 H), 6.97-7.15 (m, 3 H) , 7.27 (d, 1 H), 7.51 (d, 1 H), 7.53 (d, 1 H); Mass spectrum (ESI +) m / z 460 (M + H) + of C26H29N5O3.

  3- (1,1′-biphenyl-4-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, 2,4-oxadiazol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.93 (m, 2 H), 2.05 (m, 2 H), 2.58 (m, 2 H), 2.75 (m, 5 H), 2.85-2.92 (m, 1 H) , 3.28-3.43 (m, 2 H), 3.46 (m, 2 H), 3.79 (m, 1 H), 6.47 (d, 1 H), 7.30-7.43 (m, 6 H), 7.53-7.57 (m , 4 H); Mass spectrum of C29H30N4O3 (ESI +) m / z 483 (M + H) +.

  3- (3-Bromophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.96 (m, 2 H), 2.08 (m, 2 H), 2.68-2.91 (m, 8 H), 3.24-3.42 (m, 2 H), 3.52 (m, 2 H), 3.71 (m, 1 H), 6.58 (d, 1 H), 7.20-7.24 (m, 1 H), 7.26-7.30 (m, 1 H), 7.32-7.38 (m, 1 H), 7.46 (m, 1 H), 7.59 (d, 1 H); Mass spectrum of C23H25BrN4O3 (ESI +) m / z 485 (M + H) +.

  3- (4-Bromophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.96 (m, 2 H), 2.05-2.11 (m, 2 H), 2.65-2.77 (m, 5 H), 2.80-2.88 (m, 3 H), 3.23-3.39 (m, 2 H), 3.53 (m, 2 H), 3.71 (m, 1 H), 6.57 (d, 1 H), 7.22 (d, 2 H), 7.42 (d, 2 H), 7.58 (d , 1 H); Mass spectrum of C23H25BrN4O3 (ESI +) m / z 485 (M + H) +.

  3- (3-phenoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.96 (m, 2 H), 2.08 (m, 2 H), 2.67-2.89 (m, 8 H), 3.23-3.29 (m, 1 H), 3.48 (m, 2 H), 3.71 (m, 1 H), 6.58 (d, 1 H), 6.89-6.92 (m, 3 H), 7.03-7.15 (m, 2 H), 7.25-7.37 (m, 3 H), 7.54 (d, 1 H); Mass spectrum of C29H30N4O4 (ESI +) m / z 499 (M + H) +.

  Hydrochloric acid 3- [3- (benzyloxy) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 -Oxadiazol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.94 (m, 2 H), 2.09 (m, 2 H), 2.64-2.83 (m, 8 H), 3.22-3.32 (m, 2 H), 3.46 (m, 2 H), 3.71 (m, 1 H), 5.08 (s, 2 H), 6.53 (d, 1 H), 6.83-6.95 (m, 3 H), 7.20-7.23 (m, 1 H), 7.30-7.49 (m, 6 H); Mass spectrum of C30H32N4O4 (ESI +) m / z 513 (M + H) +.

  3- (3-Bromo-4-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, trifluoroacetic acid, 2,4-oxadiazol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.95-2.09 (m, 4 H), 2.65-2.76 (m, 4 H), 2.82-2.87 (m, 4 H), 3.21-3.28 (dd, 1 H), 3.53 (m, 2 H), 3.65 (m, 1 H), 3.83 (s, 3 H), 6.56 (d, 1 H), 6.94 (d, 1 H), 7.24 (dd, 1 H), 7.43 (d , 1 H), 7.59 (d, 1 H); Mass spectrum (ESI +) m / z 515 (M + H) + of C24H27BrN4O4.

  Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3- (3,4,5-trimethoxyphenyl) butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.95-2.11 (m, 4 H), 2.67 (t, 2 H), 2.72-2.79 (m, 3 H), 2.82-2.88 (m, 3 H), 3.25-3.39 (m, 2 H), 3.52 (m, 2 H), 3.69 (m, 1 H), 3.71 (s, 3 H), 3.82 (s, 6 H), 6.54-6.57 (m, 3 H), 7.57 (d, 1 H); C26H32N4O6 Mass spectrum (ESI +) m / z 497 (M + H) +.

  3- (2-Naphtyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole hydrochloride -5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.93-2.00 (m, 4 H), 2.46-2.52 (m, 2 H), 2.68 (t, 2 H), 2.78-2.88 (m, 3 H), 2.94 (dd , 1 H), 3.36-3.53 (m, 4 H), 3.91 (m, 1 H), 6.39 (d, 1 H), 7.39-7.49 (m, 4 H), 7.70-7.81 (m, 4 H) ; mass spectrum of _{C 27 H 28 N 4 O 3} (ESI +) m / z 457.6 (M + H) +.

  3- (3-Nitrophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.96-2.05 (m, 4 H), 2.69 (t, 2 H), 2.74 (t, 2 H), 2.80-2.86 (m, 3 H), 2.95 (dd, 1 H), 3.35 (dd, 1 H), 3.94 (dd, 1 H), 3.52 (m, 2 H), 3.39 (m, 1 H), 6.58 (d, 1 H), 7.53-7.61 (m, 2 H), 7.77 (m, 1 H), 8.07 (m, 1 H), 8.16 (m, 1 H); C ₂₃ H ₂₅ N ₅ O ₅ mass spectrum (ESI +) m / z 452.5 (M + H) ⁺ .

  3- (3-Methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.97 (m, 2 H), 2.08 (m, 2 H), 2.29 (s, 3 H), 2.67-2.76 (m, 5 H), 2.80-2.85 (m, 3 / H), 3.25 (dd, 1 H), 3.34 (dd, 1 H), 3.51 (m, 2 H), 3.69 (m, 1 H), 6.59 (d, J = 1 Hz, H), 7.00- 7.18 (m, 4 H), 7.57 (d, 1 H); mass spectrum (ESI +) m / z 421.5 (M + H) ^{+ of} C ₂₄ H ₂₈ N ₄ O ₃ .

  3- (2-Furyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole hydrochloride -5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.97 (m, 2 H), 2.12 (m, 2 H), 2.67-2.85 (m, 8 H), 3.24-3.38 (m, 2 H), 3.52 (m, 2 H), 3.83 (m, 1 H), 6.13 (d, 1 H), 6.30 (dd, 1 H), 6.61 (d, 1 H), 7.40 (d, 1 H), 7.57 (d, 1 H) ; Mass spectrum (ESI +) m / z 397.1 (M + H) ^{+ of} C ₂₁ H ₂₄ N ₄ O ₄ .

  3- (2-Methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid:

¹ H NMR (CD ₃ OD) δ 1.97 (m, 2 H), 2.05-2.13 (m, 2 H), 2.41 (s, 3 H), 2.66-2.87 (m, 8 H), 3.22-3.35 (m , 2 H), 3.52 (m, 2 H), 4.06 (m, 1 H), 6.57 (d, 1 H), 7.05-7.20 (m, 3 H), 7.29 (d, 1 H), 7.58 (d , 1 H); Mass spectrum of C ₂₄ H ₂₈ N ₄ O ₃ (ESI +) m / z 421.2 (M + H) ⁺ .
Reaction scheme 17a

  3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid, preparation of TFA

Process 1
3-Hydroxy-6-methyl-2-nitropyridine (30 g, 194.6 mmol) was added in ethanol solution at 50 ° C. with 5 atmospheres of H ₂ and 20% Pd (OH) ₂ / C catalyst for 1 hour. Hydrogenated. At the end of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the desired product (23.68 g, 98%) as a brown solid. The NMR data was consistent with the proposed structure.

Process 2
To a stirred, cooled (0 ° C.) mixture of the product from step 1 (0.500 g), 0.810 g NaHCO ₃ and 4 mL 2-butanone in 4 mL water is added 0.37 mL chloroacetyl chloride dropwise. did. When the addition was complete, the reaction mixture was warmed to room temperature, stirred for 30 minutes, and then heated to 75 ° C. for 2 hours. The reaction mixture was cooled to room temperature and 2-butanone was removed under reduced pressure. 1 mL of water was added and the solid was filtered off and washed with water to give the crude product. This solid was dissolved in warm (50 ° C.) ethyl acetate and filtered through a small plug of silica gel. The silica gel was further washed with hot ethyl acetate, combined with the filtrate and concentrated under reduced pressure to give the desired product (0.250 g, 38%) as a deep orange solid. The NMR data was consistent with the proposed structure. 1 H NMR (400 MHz, CDCl ₃ ) δ 2.45 (s, 3H), 4.64 (s, 2H), 6.78 (d, 1H), 7.15 (d, 1H).

Process 3
LiAlH ₄ (0.289 g) was slowly added to 15 mL of dry THF in a round bottom flask equipped with a stir bar and condenser. After stirring for 10 minutes, a solution of the product obtained in Step 2 (1.00 g) in 15 mL of dry THF was added dropwise. When the addition was complete, the reaction mixture was refluxed for 16 hours. The reaction was cooled to room temperature and quenched with 1M NaOH solution until the mixture became milky yellow. The precipitate was filtered off and washed 3 times with CH ₂ Cl ₂ . The filtrate and washings were combined together, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a pale yellow oil that solidified on standing. The NMR data was consistent with the proposed structure. H NMR (400 MHz, CDCl ₃ ) δ 2.30 (s, 3H), 3.53 (m, 2H), 4.20 (t, 2H), 4.88 (s, 1H), 6.49 (d, 1H), 6.86 (d, 1H ).

Process 4
A solution of the product obtained in step 3 (2.96 g), di-tert-butyl dicarbonate (4.302 g) and triethylamine (2.75 mL) in 35 mL of DMF was stirred at 50 ° C. for 16 hours. Warmed up. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give the crude product, which was purified by chromatography on silica gel (eluent, 30/70 ethyl acetate / hexanes). The desired fractions were combined and concentrated under reduced pressure to give the desired product (1.46 g, 30%) as a yellow oil. The NMR data was consistent with the proposed structure. H NMR (400 MHz, CDCl ₃ ) δ 1.55 (s, 9H), 2.45 (s, 3H), 3.89 (t, 2H), 4.21 (t, 2H), 6.82 (d, 1H), 7.05 (d, 1H ).

Process 5
To a cooled (−78 ° C.) stirred solution of the product obtained in Step 4 (1.46 g) and diethyl carbonate (2.549 g) in 15 mL of dry THF, 8.17 mL of a lithium diisopropylamide solution (THF / ethylbenzene / 2.0M) in heptane was added dropwise. After 30 minutes, the reaction was quenched with saturated ammonium chloride solution and allowed to warm to room temperature. The mixture was extracted three times with ethyl acetate and all the organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product, which was chromatographed on silica gel (eluent, 40/60 ethyl acetate / hexane). The fractions of interest were combined and concentrated under reduced pressure to give the desired product (1.48 g, 78%) as a yellow solid. The NMR data was consistent with the proposed structure.

Step 6
In dry THF (20 mL), at room temperature to a solution of the product obtained in Step 5 (1.48 g), was added (2.0 M, 2.75 mL in THF) LiBH ₄ solution, the resulting mixture Was heated to reflux. After 16 hours, the mixture was cooled to 0 ° C. and carefully quenched with water (20 ml). After 10 minutes, the mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow solid. H NMR (400 MHz, CDCl ₃ ) δ 1.55 (s, 9H), 2.90 (t, 2H), 3.93 (t, 2H), 3.96 (m, 2H), 4.23 (m, 2H), 6.78 (d, 1H ), 7.11 (d, 1H).

Step 7
A mixture of the residue obtained in step 6 and 4M HCl in dioxane (6 mL) was stirred at room temperature for 4 hours and then concentrated under reduced temperature. The residue was chromatographed on silica gel (eluent, 94.5 / 5 / 0.5 chloroform / ethanol / ammonium hydroxide) to give a yellow solid. H NMR (400 MHz, CDCl ₃ ) δ 2.77 (t, 3H), 3.56 (m, 2H), 3.91 (t, 2H), 4.21 (t, 2H), 4.73 (s, 1H), 6.39 (d, 1H ), 6.90 (d, 1H).

Process 8
The product from step 6 (3.12 g, 11.13 mmol), triethylphosphine (3.795 g, 14.47 mmol) and imidazole (1.084 mg) in CH ₃ CN (10 mL) and dry ether (16 mL). , 15.92 mmol) was slowly added iodine (3.955 g, 15.58 mmol) to a stirred cooled (0 ° C.) solution and then stirred for 1 hour. To the resulting mixture was added 150 mL of ether, followed by washing with saturated aqueous Na ₂ S ₂ O ₃ and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, 20% EtOAC / Hex) to give a yellow solid. H NMR (400 MHz, CDCl ₃ ) δ 1.54 (s, 9H), 3.23 (t, 2H), 3.49 (t, 2H), 3.91 (t, 2H), 4.23 (t, 2H), 6.84 (d, 1H ), 7.10 (d, 1H).

Step 9
NaH (103 mg of a 60 wt% dispersion in mineral oil, 2.564 mmol) was suspended in DMF (13 mL) at 0 ° C. under N ₂ . Ethyl cyanoacetate (0.27 mL, 2.564 mmol) was added and the resulting mixture was stirred for 30 minutes at 0 ° C. The product from Step 8 (1.00 g, 2.564 mmol) in DMF (2 mL) was charged to the reaction mixture and stirred for 1 hour at room temperature. The mixture was cooled to 0 ° C., quenched with water and extracted with EtOAc (3 ×). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica, 50% EtOAC / Hex) to give a colorless oil. H NMR (400 MHz, CDCl ₃ ) δ 1.32 (t, 3H), 1.54 (s, 9H), 2.30 (m, 1H), 2.45 (m, 1H), 2.90 (m, 2H), 3.90 (m, 2H ), 3.97 (m, 1H), 4.25 (m, 4H), 6.36 (d, 1H), 7.09 (d, 1H).

Step 10
A mixture of the product from step 9 (460 mg, 1.225 mmol) and KOH (powder, 123 mg, 1.838 mmol) in ethylene glycol (2 mL) under N ₂ was heated at 150 ° C. for 3 hours. . The mixture was cooled to 0 ° C. and partitioned between water and EtAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. Flash chromatography (silica, 100% EtOAc) gave a colorless oil. H NMR (400 MHz, CDCl ₃ ) δ 2.03 (m, 2H), 2.34 (t, 2H), 2.67 (t, 2H), 3.54 (m, 2H), 4.20 (t, 2H), 6.41 (d, 1H ), 6.89 (d, 1H).

Step 11
Under N ₂ , a mixture of the product obtained in Step 10 (460 mg, 2.263 mmol) and hydroxylamine (0.329 mL of a 50 wt% solution in water, 4.98 mmol) in ethanol (6 mL) was added. Heated at 60 ° C. overnight. The mixture was cooled to room temperature and concentrated under vacuum to give a white solid.

Step 12
A mixture of the product obtained in Step 11 (550 mg, 2.263 mmol) and the product obtained in Example 1 Step 3 (529 mg, 2.263 mmol) in 1,4-dioxane (3 mL) was dissolved in 90 Heated at 0 ° C. overnight. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was purified by HPLC with a 15-50% acetonitrile gradient over 30 minutes to give 30 mg of the desired product as a yellow oil. FAB-MS: (MH +) = 453. H NMR (400 MHz, CD ₃ OD) δ 2.05 (m, 2H), 2.74 (m, 6H), 3.27 (m, 2H), 3.65 (m, 3H), 4.30 (t, 2H), 5.86 (s, 2H), 6.61 (d, 1H), 6.69 (s, 2H), 6.78 (s, 1H), 7.34 (d, 1H).

  4- {3- [3- (3,4-Dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) propyl] -1,2,4-oxadiazole-5 -Il} -3- (3,5, -dimethoxyphenyl) butanoic acid, production of TFA

A mixture of the product obtained in Example 68 step 11 (190 mg, 0.542 mmol) and the appropriate anhydride (135 mg, 0.542 mmol) in 1,4-dioxane (4 ml) was stirred at 90 ° C. overnight. Heated. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was purified by HPLC with a 15-50% acetonitrile gradient over 30 minutes to give 20 mg of the desired product as a yellow oil. FAB-MS: (MH +) = 469.H NMR (400 MHz, CD ₃ OD) δ 2.00 (m, 2H), 2.70 (m, 6 H), 3.25 (m, 2H), 3.61 (m, 3H), 3.66 (s, 6 H), 4.24 (t, 2H), 6.26 (t, 1H), 6.36 (d, 2H), 6.54 (d, 1H), 7.27 (d, 1H).
Reaction scheme 18

  3-Benzo [1,3] dioxol-5-yl-4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene-2- Yl) -propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid:

  Step 1.5-Methyl-3H-oxazolo [4,5-b] pyridin-2-one

A solution of 2-amino-6-methyl-pyridin-3-ol (0.2 g, 1.6 mmol), 1,1-carbonyldiimidazole (0.39 g, 2.4 mmol) and DMF (10 mL) was added at room temperature. Stir overnight, then dilute with water (50 mL) and extract with ethyl acetate (50 mL, 3 ×). The ethyl acetate solution was washed with water and brine and purified on a column of silica gel eluting with 10% ethyl acetate / hexane to give 120 mg of the desired product as a pale yellow solid. ¹ H-NMR (CD ₃ OD): δ 2.42 (3H, s, CH ₃ ), δ 6.92 (1H, d, Py-H), δ 7.38 (1H, d, Py-H).

  Step 2. 3- (3-Chloro-propyl) -5-methyl-3H-oxazolo [4,5-b] pyridin-2-one

A solution of NaH 60% (0.021 g, 0.51 mmol), DMF (10 mL) and 5-methyl-3H-oxazolo [4,5-b] pyridin-2-one (70 mg, 0.47 mmol) was added to room temperature at room temperature. Stir for 5 hours. 1-Bromo-3-chloropropane (0.056 mL, 0.56 mmol) was added. The resulting solution was stirred overnight at room temperature. The solution was diluted with water (50 mL) then extracted with ethyl acetate, washed with water and brine and concentrated to give 110 mg of the desired product as a yellow oil. ¹ H-NMR (CDCl ₃ ): δ 2.35 (2H, m, CH ₂ ), 2.53 (3H, s, CH ₃ ) 3.60 (2H, t, CH ₂ ) _, 4.08 (2H, t, CH ₂ ) _, 6.90 (1H, d, Py-H), 7.28 (1H, d, Py-H).

  Step 3. 2-Methyl-6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene

A mixture of 3- (3-chloro-propyl) -5-methyl-3H-oxazolo [4,5-b] pyridin-2-one (15 g), methoxyethanol (200 mL) and KOH (18.24 g) was heated. Reflux for 2 days under nitrogen. The solution was cooled to room temperature and then the solvent was removed. The residue was dissolved in a mixture of water and ethyl acetate (1: 1, 1 L). The aqueous portion was extracted well with ethyl acetate and the combined organic extracts were washed with water and brine and dried over magnesium sulfate. Removal of the solvent gave a crude product which was purified on a silica gel column eluting with 70% ethyl acetate / hexanes to give 7.7 g of the desired product as a colorless oil. ¹ H-NMR (CDCl ₃ ): δ 2.025 (2H, m, CH ₂ ), 2.35 (3H, s, CH ₃ ) 3.32 (2H, m, CH ₂ ) _, 4.10 (2H, t, CH ₂ ) _, 4.65 (1H, br s, NH) _, 6.50 (1H, d, Py-H), 7.05 (1H, d, Py-H).

  Step 4. 2-Methyl-7,8-dihydro-6H-5-oxa-1,9-diaza-benzocycloheptene-9-carboxylic acid tert-butyl ester:

2-Methyl-6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene (25.44 g, 0.155 mol), tetrahydrofuran (100 mL), di-tert-butyl dicarbonate A solution of (67.61 g, 0.31 mol) and dimethylaminopyridine (5 g) was heated to 40 ° C. for 3 hours. The solution was cooled to room temperature and then concentrated to give the crude product, which was crystallized with methanol to give 23 g of the desired product as a yellow solid. ¹ H-NMR (CDCl ₃ ): δ 1.45 (9H, s, 3XCH ₃ ), 2.05 (2H, m, CH ₂ ), 2.50 (3H, s, CH ₃ ) 3.70 (2H, br s, CH ₂ ) _, 4.10 (2H, t, CH ₂ ) _, 6.95 (1H, d, Py-H), 7.25 (1H, d, Py-H).

  Step 5. 2-Ethoxycarbonylmethyl-7,8-dihydro-6H-5-oxa-1,9-diaza-benzocycloheptene-9-carboxylic acid tert-butyl ester:

Of 2-methyl-7,8-dihydro-6H-5-oxa-1,9-diaza-benzocycloheptene-9-carboxylic acid tert-butyl ester (3.79 g, 14.34 mmol) and THF (30 mL) The solution was cooled to -78 ° C. Lithium diisopropylamide (10.75 mL, 21.51 mmol) was added. The mixture was stirred at −78 ° C. for 0.5 hour and then diethyl carbonate was added. The resulting mixture was stirred at −78 ° C. for 2 hours. The reaction was stopped by adding a saturated solution of ammonium chloride. The solution was extracted with acetic ester, washed with brine, dried over magnesium sulfate, concentrated and purified on a column of silica gel (10% ethyl acetate / hexane) to give 1.15 g of the desired product. ¹ H-NMR (CDCl ₃ ): δ 1.45 (9H, s, 3XCH ₃ ), 2.025 (2H, m, CH ₂ ), 2.35 (3H, s, CH ₃ ) 3.32 (2H, m, CH ₂ ) _, 4.10 _{(2H, t, CH 2)} , 4.65 (1H, br s, NH), 6.50 (1H, d, Py-H), 7.05 (1H, d, Py-H).

  Step 6. 2- (2-Hydroxy-ethyl) -7,8-dihydro-6H-5-oxa-1,9-diaza-benzocycloheptene-9-carboxylic acid tert-butyl ester:

2-Ethoxycarbonylmethyl-7,8-dihydro-6H-5-oxa-1,9-diaza-benzocycloheptene-9-carboxylic acid tert-butyl ester (1.67 g, 5.00 mmol), THF (50 mL ) And lithium borohydride (4.96 mL, 9.93 mmol) were heated to reflux overnight. The reaction was quenched with water, extracted with acetate, washed with brine, concentrated and purified on a silica gel column (40% ethyl acetate / hexanes) to yield 1.07 g of the desired product. ¹ H-NMR (CD ₃ OD): δ 1.45 (9H, s, 3XCH ₃ ), 2.08 (2H, m, CH ₂ ), 2.95 (2H, t, CH ₂ ), 3.70 (2H, br s, CH ₂ ) _, 3.85 (2H, t, CH ₂ ) _, 4.10 (2H, br s, CH ₂ ) _, 7.20 (1H, d, Py-H), 7.45 (1H, d, Py-H).

  Step 7. 2- (2-Iodo-ethyl) -7,8-dihydro-6H-5-oxa-1,9-diaza-benzocycloheptene-9-carboxylic acid tert-butyl ester:

2- (2-Hydroxy-ethyl) -7,8-dihydro-6H-5-oxa-1,9-diaza-benzocycloheptene-9-carboxylic acid tert-butyl ester (0.20 g, 0.68 mmol) A solution of acetonitrile / ether (1: 1, 30 mL), triphenylphosphine (0.23 g, 0.88 mmol), imidazole (0.06 g, 0.98 mmol) was cooled to 0 ° C. Iodine (0.24 g, 0.95 mmol) was added. The mixture was stirred at −78 ° C. for 0.5 hour and then diethyl carbonate was added. The resulting mixture was stirred at 0 ° C. for 2 hours. Saturated aqueous sodium sulfate solution was added to stop the reaction. The solution was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, concentrated and purified on a silica gel column (30% ethyl acetate / hexanes) to give 0.223 g of the desired product. ¹ H-NMR (CDCl ₃ ): δ 1.39 (9H, s, 3XCH ₃ ), δ 2.03 (2H, m, CH ₂ ), δ 3.23 (2H, t, CH ₂ ), δ 3.42 (2H, t, CH ₂ ), δ 3.68 (2H, br s, CH ₂ ), δ 4.08 (2H, m, CH ₂ ), δ 6.92 (1H, d, Py-H), δ 7.22 (1H, d, Py-H).

  Step 8. 2- (3-Cyano-3-ethoxycarbonyl-propyl) -7,8-dihydro-6H-5-oxa-1,9-diaza-benzocycloheptene-9-carboxylic acid tert-butyl ester

A solution of NaH (0.1 g, 2.52 mmol) and DMF (15 mL) was cooled to 0 ° C. Ethyl cyanoacetate (0.27 mL, 2.52 mmol) was added. The mixture was stirred at 0 ° C. for 0.5 h and then 2- (2-iodo-ethyl) -7,8-dihydro-6H-5-oxa-1, in DMF (0.68 g, 1.68 mmol). 9-diaza-benzocycloheptene-9-carboxylic acid tert-butyl ester was added. The resulting mixture was stirred at 0 ° C. for 1 hour. The reaction was stopped by adding water. The solution was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, concentrated and purified on a silica gel column (10% ethyl acetate / hexane) to give 0.2 g of the desired product. ¹ H-NMR (CDCl ₃ ): δ 1.30 (3H, t, CH ₃ ), δ 1.45 (9H, s, 3XCH ₃ ), δ 2.15 (2H, m, CH ₂ ), δ 2.45 (2H, m, CH ₂ ), δ 3.05 (2H, m, CH ₂ ) _, δ 3.70 (2H, br s, CH ₂ ) _, δ 3.80 (2H, m, CH ₂ ), δ 4.15 (2H, m, CH ₂ ) _, δ 4.30 (2H, q, CH ₂ ) _, δ 6.95 (1H, d, Py-H), δ 7.30 (1H, d, Py-H).

  Step 9.4- (6,7,8,9-Tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl) -butyronitrile

2- (3-Cyano-3-ethoxycarbonyl-propyl) -7,8-dihydro-6H-5-oxa-1,9-diaza-benzocycloheptene-9-carboxylic acid tert-butyl ester (0.27 g , 0.58 mmol), ethylene glycol (20 mL) and KOH powder (0.058 g, 1.04 mmol) were heated at 150 ° C. for 3 hours. The reaction was quenched with water and the solution was extracted with ethyl acetate, washed with brine, concentrated and purified on a silica gel column (ethyl acetate) to give 0.146 g of the desired product. ¹ H-NMR (CDCl ₃ ): δ 1.45 (9H, s, 3XCH ₃ ), δ 2.08 (2H, m, ¹ H-NMR (CD ₃ OD): δ 2.04 (2H, m, CH ₂ ), δ 2.06 (2H, t, CH ₂ ), δ 2.36 (2H, t, CH ₂ ), δ 2.70 (2H, t, CH ₂ ) _, δ 3.35 (2H, m, CH ₂ ) _, δ 4.10 (2H, t, CH ₂ ) _, δ 4.84 (1H, s, NH) _, δ 6.52 (1H, d, Py-H), δ 7.08 (1H, d, Py-H).

  Step 10. N-hydroxy-4- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl) -butyramidine

To methanol (7 mL) at room temperature under N ₂ was added Na (154 mg, 6.7 mmol). After the Na was dissolved in methanol, NH ₂ OH hydrochloride (465 mg, 6.7 mmol) was added. The resulting solution was stirred for 2 hours under N ₂ and then filtered. The filtrate is added to 4- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl) -butyronitrile and the mixture is heated at 40 ° C. overnight. did. The solvent was removed. The crude product was purified by reverse phase HPLC with a gradient of acetonitrile / water (1%) to give 168 mg of the desired product as a white solid. ¹ H-NMR (CD ₃ OD): δ 2.08 (2H, m, CH ₂ ), 2.25 (2H, m, CH ₂ ), 2.50 (2H, t, CH ₂ ), 2.80 (2H, t, CH ₂ ) _{, 3.70 (2H, m, CH} 2), 3.85 (2H, t, CH 2), 6.67 (1H, d, Py-H), 7.48 (1H, d, Py-H).

  Step 11. 3-Benzo [1,3] dioxol-5-yl-4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene -2-yl) -propyl]-[1,2,4] -oxadiazol-5-yl} -butyric acid:

N-hydroxy-4- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl) -butyridine (168 mg, 0.46 mmol), 4-benzo [ A solution of 1,3] dioxol-5-yl-dihydro-pyran-2,6-dione (129 mg, 0.55 mmol), dioxane (15 mL) and triethylamine (0.13 mL, 0.92 mmol) was added under N ₂ . Heated to 95 ° C. overnight. The solvent was removed. The crude product was purified by reverse phase HPLC with a gradient of acetonitrile / water (5%) to give 0.093 g of the desired product as a colorless oil. ¹ H-NMR (CD ₃ CN): δ 1.93 (2H, m, CH ₂ ), 2.58 (2H, m, CH ₂ ), 2.50 (2H, m, CH ₂ ), 2.60 (2H, m, CH ₂ ) , 2.70 (2H, m, CH ₂ ), 3.24 (2H, m, CH ₂ ) _, 3.49 (1H, m, CH) _, 3.58 (2H, t, CH ₂ ) _, 4.23 (2H, t, CH ₂ ), 5.93 (2H, s, CH ₂ ), 6.60 (1H, d, Py-H), 6.68 (1H, d, Ar-H), 6.74 (1H, d, Ar-H), 6.90 (1H, s, Ar -H), 7.42 (1H, d, Py-H) .C ₂₄ H ₂₆ N ₄ O _6.1.5 TFA, 1.0 H ₂ O calculated: C, 49.47; H, 4.54; N, 8.55, found: C, 49.47; H, 4.62; N, 8.78.

  3- (3-Fluoro-4-methoxyphenyl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl ) -Propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid

The title compound was prepared in Step 11 using the appropriate anhydride according to the preparation method of Example 70. ¹ H-NMR (CD ₃ CN): δ 1.93 (2H, m, CH ₂ ), 2.00 (2H, m, CH ₂ ), 2.18 (2H, m, CH ₂ ), 2.65 (2H, m, CH), 2.78 (2H, m, CH ₂ ) _, 3.20 (2H, m, CH ₂ ) _, 3.58 (1H, m, CH) _, 3.61 (2H, t, CH ₂ ), 3.80 (3H, s, CH ₃ ) _, 4.28 (2H, t, CH ₂ ), 6.48 (1H, d, Py-H), 7.00 (3H, m, Ar-H), 7.32 (1H, s, Py-H). C ₂₄ H ₂₇ FN ₄ O _{5 ..} 1.3 Calculated for TFA, 1.0 H ₂ O: C, 50.18; H, 4.80; N, 8.80, found: C, 50.27; H, 4.48; N, 9.13.

  3- (3,5-difluorophenyl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl)- Propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid

The title compound was prepared according to the preparation method of Example 70, using the appropriate anhydride in Step 11. ¹ H-NMR (CD ₃ CN): δ 1.93 (2H, m, CH ₂ ), 2.00 (2H, m, CH ₂ ), 2.18 (2H, m, CH ₂ ), 2.67 (2H, m, CH), 2.75 (2H, m, CH ₂ ) _, 3.22 (2H, m, CH ₂ ) _, 3.60 (2H, t, CH ₂ ), 3.68 (1H, m, CH), 4.28 (2H, t, CH ₂ ) _, 6.50 (1H, d, Pyr-H), 6.78 (1H, m, Ar-H), 6.90 (2H, m, Ar-H), 7.35 (1H, s, Py-H). C ₂₃ H ₂₄ F ₂ N _{. 4 O 4 1.4 TFA, 1.0} H 2 O calculated: C, 48.72; H, 4.07 ; N, 9.02, Found: C, 48.47; H, 4.07 ; N, 9.02.

  3- (3,5-Dimethoxyphenyl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl)- Propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid

The title compound was prepared according to the preparation method of Example 70 using the appropriate anhydride from Step 11. ¹ H-NMR (CD ₃ CN): δ 1.93 (2H, m, CH ₂ ), 2.00 (2H, m, CH ₂ ), 2.18 (2H, m, CH ₂ ), 2.65 (2H, m, CH), 2.75 (2H, m, CH ₂ ) _, 3.20 (2H, m, CH ₂ ) _, 3.58 (1H, m, CH) _, 3.61 (2H, t, CH ₂ ), 3.70 (6H, s, 2XCH ₃ ) _, 4.28 (2H, t, CH ₂ ), 6.30 (1H, m, Ar-H), 6.38 (2H, d, Ar-H), 6.50 (1H, d, Py-H), 7.32 (1H, s, Py- _{.. H) C 25 H 30} N 4 O 6 1.4 TFA, 0.8 H 2 O calculated: C, 50.86; H, 5.07 ; N, 8.53, Found: C, 50.77; H, 4.98 ; N, 8.89.

  3- (2-Methylbenzothiazol-5-yl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene-2- Yl) -propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid:

The title compound was prepared in Step 11 using the appropriate anhydride according to the preparation method of Example 70. ¹ H-NMR (CD ₃ CN): δ 1.93 (2H, m, CH ₂ ), 1.95 (2H, m, CH ₂ ), 2.18 (2H, m, CH ₂ ), 2.60 (2H, m, CH), 2.72 (3H, s, CH ₃ ), 2.85 (2H, m, CH ₂ ) _, 3.30 (2H, m, CH ₂ ) _, 3.60 (2H, t, CH ₂ ), 3.78 (1H, m, CH) _, 4.28 (2H, t, CH ₂ ), 6.42 (1H, d, Py-H), 7.25 (1H, d, Ar-H), 7.30 (1H, d, Ar-H), 7.78 (1H, s, Ar- _{.. H), 7.80 (1H} , s, Py-H) C 25 H 27 N 5 O 4 S 1.3 TFA, 1.0 H 2 O calculated: C, 50.24; H, 4.63 ; N, 10.61, Found: C, 50.34; H, 4.37; N, 10.56.

  3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (1,2,3,5-tetrahydropyrido [2,3-e] [1,4] oxazepine -8-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid, preparation of TFA

Reaction scheme 19

  Process 1

To a 1M solution of borane-tetrahydrofuran complex (200 mL, 200 mmol) under N ₂ at 0 ° C. was added 2-chloro-6-methylnicotinic acid (15 g, 87.42 mmol) in dry THF (45 mL) using a dropping funnel. Added. After completion of the addition, the ice bath was removed and the reaction was allowed to proceed overnight with stirring. A mixture of acetic acid (12 mL) and methanol (12 mL) was added dropwise to the reaction flask at 0 ° C. and stirred for 1 hour. Volatiles were removed in vacuo and the residue was dissolved in water. The solution was neutralized with 1N NaOH and then extracted with EtOAc (3 times). The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to give the title compound as a white solid. 1 H NMR (400 MHz, CDCl ₃ ) d 2.53 (s, 3H), 4.75 (s, 2H), 7.13 (d, 1H), 7.74 (d, 2H).

  Process 2

To a solution of the product obtained in step 1 (10 g, 63.7 mmol) in CH ₂ Cl ₂ (150 mL) at room temperature under Ar, thionyl chloride (16.3 mL, 223 mmol) was added and the mixture Was stirred for 4 hours. This mixture was poured very slowly into ice water. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (twice). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the title compound as a white solid. 1 H NMR (400 MHz, CDCl ₃ ) d 2.55 (s, 3H), 4.68 (s, 2H), 7.13 (d, 1H), 7.71 (d, 2H).

  Process 3

To a solution of t-butyl N- (2-hydroxyethyl) -carbamate (8.41 g, 52.2 mmol) in DMSO (30 mL) at room temperature, KOH powder (5.86 g, 104.4 mmol) was added, The product obtained in step 2 (6 g, 34 mmol) was then added. After stirring at room temperature for 2 hours, the reaction was quenched with water. After extraction with Et ₂ O (3 times), the organic layer is washed and partitioned between water and EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo as a yellow oil. The title compound was obtained. H NMR (400 MHz, CDCl ₃ ) d 1.45 (s, 9H), 2.56 (s, 3H), 3.40 (m, 2H), 3.64 (t, 2H), 4.57 (s, 2H), 7.20 (d, 1H ), 7.29 (d, 2H).

  Process 4

Pyridine from step 3 (8.8 g, 29.3 mmol) and mCPBA (7.6 g, 43.98 mmol) were dissolved in CHCl ₃ and stirred at 50 ° C. overnight. The solution was concentrated in vacuo and purified by flash chromatography (silica, 98: 2: 0.5 = CH ₂ Cl ₂ : MeOH: NH ₄ OH) to give a yellow oil. H NMR (400 MHz, CDCl ₃ ) d 1.44 (s, 9H), 2.56 (s, 3H), 3.40 (m, 2H), 3.64 (t, 2H), 4.56 (s, 2H), 7.22 (d, 1H ), 7.32 (d, 2H).

  Process 5

  The product of step 4 (5.3 g, 16.8 mmol) was dissolved in HCl-EtOH solution (35 mL) at room temperature and stirred overnight. The reaction was concentrated to dryness to give a white solid.

  Step 6

To a solution of the product obtained in step 5 (4.23 g, 16.8 mmol) in t-amyl-alcohol (30 mL) at room temperature under N ₂ was added NaHCO ₃ (7.05 g, 84 mmol). The mixture was heated to reflux overnight. The reaction was cooled, diluted with CH ₂ Cl ₂ and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica, 98: 2: 0.5 = CH ₂ Cl ₂ : MeOH: NH ₄ OH) to give pale yellow crystals. H NMR (400 MHz, CDCl ₃ ) δ 2.54 (s, 3H), 3.40 (m, 2H), 3.90 (t, 2H), 4.60 (s, 2H), 6.63 (d, 1H), 6.93 (d, 2H ).

  Step 7

The product obtained in step 6 (3.47 g, 19.28 mmol), ion powder (1.62 g, 28.9 mmol), triphenylphosphine (5.06 g, 19.28 mmol) and acetic acid (50 mL) The solution was heated to reflux for 1 hour. The solution was cooled, filtered through a celite bed and washed with ethyl acetate. The filtrate was concentrated and purified by silica gel column (eluting with 97.5: 2: 0.5 dichloromethane / methanol / ammonium hydroxide) to give pale yellow crystals. H NMR (400 MHz, CDCl ₃ ) δ 2.40 (s, 3H), 3.26 (m, 2H), 3.84 (t, 2H), 4.53 (s, 2H), 6.59 (d, 1H), 7.82 (d, 2H ).

  Process 8

Heat a solution of the product obtained in step 7 (3.4 g, 20.7 mmol), di-tert-butyl dicarbonate (9.05 g, 41.46 mmol) and DMAP (251 mg) in THF (100 mL). And refluxed overnight. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was crystallized from 20% EtOAc / hexanes to give a brown solid. H NMR (400 MHz, CDCl ₃ ) δ 1.45 (s, 9H), 2.54 (s, 3H), 3.90 (m, 2H), 4.55 (s, 2H), 7.01 (d, 1H), 7.50 (d, 2H ).

  Step 9

To a cooled (−78 ° C.) stirred solution of the product obtained in step 8 (2.1 g, 7.95 mmol) in dry THF (30 mL) was added lithium diisopropylamide solution (4.7 mL, 9) under N _2. .54 mmol, 2.0 M in THF / ethylbenzene / heptane) was added dropwise and the resulting solution was stirred at −78 ° C. for 20 minutes. To this mixture was added diethyl carboxylate (3.6 mL, 29.41 mmol). After 1 hour, the reaction was quenched with saturated NH ₄ Cl solution and allowed to warm to room temperature. The mixture was extracted three times with ethyl acetate and all the organic extracts were combined together, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product. The product was purified by chromatography on silica gel (eluent, 25% ethyl acetate / hexane). The desired product is a yellow solid. H NMR (400 MHz, CDCl ₃ ) δ 1.27 (t, 3H), 1.44 (s, 9H), 3.83 (s,), 4.16 (q, 2H), 4.57 (s, 2H), 7.19 (d, 1H) , 7.60 (d, 2H).

  Step 10

To the solution of the product obtained in step 9 (1.9 g, 5.7 mmol) in dry THF (25 mL) at room temperature was added LiBH ₄ solution (2.0 M in THF, 3.4 mL, 6.78 mmol). Was added and the resulting mixture was heated to reflux. After 16 hours, the mixture was cooled to 0 ° C. and the reaction was carefully quenched with water (20 mL). After 10 minutes, the mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow solid. H NMR (400 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 3.01 (t, 2H), 3.90 (m, 2H), 4.00 (m, 2H), 4.57 (s, 2H), 7.03 (d, 1H ), 7.56 (d, 1H).

Step 11
A mixture of the product from step 10 and 4M HCl in dioxane (6 mL) was stirred at room temperature for 4 hours and then concentrated at low temperature. The residue was chromatographed on silica gel (eluent, 94.5: 5: 0.5 chloroform / ethanol / ammonium hydroxide) to give a yellow oil. H NMR (400 MHz, CDCl ₃ ) δ 3.11 (t, 2H), 3.63 (m, 2H), 3.96 (m, 2H), 4.05 (t, 3H), 4.67 (s, 2H), 6.74 (d, 1H ), 7.60 (d, 1H).

  Step 12

The product from step 10 (1.26 g, 4.28 mmol), triphenylphosphine (1.46 g, 5.56 mmol) and imidazole (417 mg, in CH ₃ CN (6 mL) and dry ether (8 mL). To a stirred and cooled (0 ° C.) solution of 6.12 mmol) iodine (1.52 g, 6 mmol) was added slowly and stirred for 1 hour. The resulting mixture was added to 100 mL of ether, washed successively with saturated Na ₂ S ₂ O ₃ solution and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, 20% EtOAC / Hex) to give a yellow solid. H NMR (400 MHz, CDCl ₃ ) δ 1.45 (s, 9H), 3.35 (t, 2H), 3.50 (t, 2H), 3.92 (s, 2H), 4.57 (s, 2H), 7.04 (d, 1H), 7.57 (d, 1H).

  Step 13

NaH (208 mg, 5.19 mmol of a 60 wt% dispersion in mineral oil) was suspended in DMF (15 mL) under N _{2 at} 0 ° C. Ethyl cyanoacetate (0.405 mL, 3.8 mmol) was added and the resulting mixture was stirred at 0 ° C. for 30 minutes. The product from step 12 (1.4 g, 3.46 mmol) in DMF (2 mL) was charged to the reaction mixture and stirred at room temperature for 1 hour. The mixture was cooled to 0 ° C., quenched with water and extracted with EtOAc (3 ×). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica, 50% EtOAC / Hex) to give a colorless oil. H NMR (400 MHz, CDCl ₃ ) δ 1.32 (t, 3H), 1.44 (s, 9H), 2.31 (m, 1H), 2.50 (m, 1H), 3.00 (m, 2H), 3.66 (m, 1H ), 3.90 (s, 2H), 4.26 (q, 2H), 4.57 (s, 2H), 7.05 (d, 1H), 7.55 (d, 1H).

  Step 14

A mixture of the product obtained in Step 13 (700 mg, 1.8 mmol) and KOH (powder, 152 mg, 2.7 mmol) in ethylene glycol (8 mL) under N ₂ was heated at 150 ° C. for 3 hours. The mixture was cooled to 0 ° C. and partitioned between water and EtOAc. The organic phase was washed with brine and the residue was washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash chromatography (silica, EtOAc) gave a pale yellow oil. H NMR (400 MHz, CDCl ₃ ) δ 2.07 (t, 3H), 2.37 (t, 1H), 2.77 (t, 2H), 3.24 (m, 2H), 3.85 (m, 2H), 4.53 (s, 2H), 4.98 (s, 1H), 6.61 (d, 1H), 7.33 (d, 1H).

  Step 15

Under N ₂ , a mixture of the product obtained in step 14 (270 mg, 1.24 mmol) and hydroxylamine (0.18 mL of a 50 wt% solution in water, 2.73 mmol) in ethanol (4 mL) was added. Heated at 60 ° C. overnight. The mixture was cooled to room temperature and concentrated in vacuo to give a white solid.

  Step 16

A mixture of the product obtained in Step 15 (110 mg, 0.44 mmol) and the anhydride from Example 1 Steps 1-3 (93 mg, 0.4 mmol) in 1,4-dioxane (3 mL) was added to 90 Heated at 0 ° C. overnight. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was purified by HPLC with 1 acetonitrile gradient 15-50% over 30 minutes to give 56 mg of the desired product as a yellow oil. FAB-MS: (MH +) = 467.H NMR (500 MHz, CD ₃ OD) δ 2.08 (m, 2H), 2.72 (m, 5H), 3.26 (m, 2H), 3.61 (m, 1H), 3.68 (t, 2H), 3.98 (t, 2H), 4.25 (s, 2H), 5.84 (m, 2H), 6.67 (m, 2H), 6.76 (s, 2H), 6.79 (d, 1H), 7.78 ( d, 1H). 1.3 Analysis result of C ₂₄ H ₂₆ N ₄ O ₆ with CF ₃ COOH added, calculated value: C, 51.98; H, 4.48; N, 9.11. Theoretical value: 51.67; H, 4.54; N, 9.24.

  3- (3,5-Dimethoxyphenyl) -4- {3- [3- (1,2,3,5-tetrahydropyrido [2,3-e] [1,4] oxazepin-8-yl) propyl ] -1,2,4-oxadiazol-5-yl} butanoic acid, production of TFA

Prepared from the product obtained in Example 15 Step 15 (176 mg, 0.70 mmol) in 1,4-dioxane (4 mL) and 3,5-dimethoxybenzaldehyde as in Example 1 Steps 1-3. A mixture of the appropriate anhydride (160 mg, 0.63 mmol) was heated at 90 ° C. overnight. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was purified by HPLC with an acetonitrile gradient of 15-50% over 30 minutes to give 35 mg of the desired product as a yellow oil. FAB-MS: (MH +) = 483.H NMR (500 MHz, CD ₃ OD) δ 2.08 (m, 2H), 2.74 (m, 5H), 3.28 (m, 2H), 3.62 (m, 1H), 3.69 (m, 8H), 3.78 (m, 1H), 4.00 (t, 2H), 4.84 (s, 2H), 6.27, (t, 1H), 6.37 (d, 2H), 6.77 (d, 1H), 7.77 (d, 1H).

  Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] -propyl} -1,2,4-oxa Diazol-5-yl) butanoic acid:

Reaction scheme 20a

  Step 1: 6-Bromo-N-methylpyridin-2-amine

Sodium hydride (95%, 1.0108 g) was suspended in THF (25 mL) under a nitrogen atmosphere. To this mixture was slowly added a solution of 2-amino-6-bromopyridine (7.3 g) in THF (50 mL) at room temperature. The mixture was stirred at ambient temperature for 30 minutes. The mixture was quenched with iodomethane (5.0 mL). The reaction mixture was stirred at room temperature for 30 minutes before being quenched with water and extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give a crude oil which is purified by chromatography on silica gel (Biotage Flash 40M) to give the title compound as a pale yellow oil. Obtained. ¹ HNMR (CD ₃ OD): δ 7.95 (t, 1H), 7.65 (m, 1H), 7.42 (d, 1H), 7.05 (d, 1H), 3.55 (d, 3H).

  Step 2: 4- [6- (Methylamino) pyridin-2-yl] -butanenitrile

The product of step 1 (3.45 g, 20 mmol) was dissolved in THF (50 mL) and treated with tetrakis (triphenylphosphine) palladium (0). The mixture was stirred at ambient temperature under a nitrogen atmosphere for 15 minutes and treated with a 0.4 M solution of 3-cyanopropylzinc bromide in THF. The mixture was quenched with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give a crude oil which was purified by reverse phase HPLC (water and 2% TFA / CH ₃ CN mobile phase). To give 1.4 g of the title compound as a TFA salt. ¹ HNMR (CD ₃ OD): δ 7.75 (t, 1H), 6.65 (m, 2H), 3.05 (s, 3H), 2.82 (t, 2H), 2.45 (t, 2H), 2.1 (m, 2H) .

  Step 3: N-hydroxy-4- [6- (methylamino) pyridin-2-yl] -butaneimidamide:

Metallic sodium (0.715 g, 31 mmol) was dissolved in MeOH (30 mL) under a nitrogen atmosphere and hydroxylamine hydrochloride (2.16 g) was added to the mixture. The mixture was stirred at ambient temperature under a nitrogen atmosphere for 2 hours. The solid is filtered under vacuum and the filtrate is added to the free base of the product from step 2, heated to 41 ° C. and stirred at 41 ° C. for 48 hours, and the mixture is quenched with water (1 mL). And concentrated to give a crude oil which was purified by reverse phase HPLC (water and 2% TFA / CH ₃ CN mobile phase) to give 0.520 g of the title compound as a TFA salt. ¹ HNMR (CD ₃ OD): δ 7.55 (m, 1H), 6.55 (m, 2H), 3.45 (s, 3H), 2.72 (t, 2H), 2.35 (t, 2H), 2.1 (m, 2H) .

  Step 4: Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] propyl} -1,2,4 -Oxadiazol-5-yl) butanoic acid

The product from step 3 (322 mg) was dissolved in dioxane (5 mL) containing triethylamine (200 mg) and treated with the appropriate anhydride (210 mg, as in Example 1) in a scintillation vial and treated at 90 ° C. for 16 Heated for hours. The mixture was concentrated to give a crude oil that was purified by reverse phase HPLC (water and 2% HCl / CH ₃ CN mobile phase) to give 0.120 g of the title compound as the HCl salt. ¹ HNMR (CD ₃ OD): δ 7.85 (t, 1H), 6.92 (d, 1H), 6.78 (s, 1H), 6.68 (m, 3H), 5.87 (s, 2H), 3.62 (m, 1H) 3.25 (m, 1H), 3.05 (s, 3H), 2.75 (m, 6H), 2.10 (m, 2H). Mass spectrum: (MH +): 425.2.

  3- (3-Fluorophenyl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] propyl} -1,2,4-oxadiazol-5-yl) trifluoroacetate Butanoic acid:

According to the method described in Step 4 of Example 77, the above compound was prepared using the appropriate anhydride. ¹ HNMR (CD ₃ OD): δ 7.85 (t, 1H), 7.28 (m, 1H), 7.10 (d, 1H), 7.05 (m, 1H), 6.88 (m, 2H), 6.7 (d, 1H) , 3.72 (m, 1H), 3.35 (m, 2H), 3.05 (s, 3H), 2.75 (m, 6H), 2.10 (m, 2H). Mass spectrum: (MH +): 399.2.

  3- (1,3-Benzodioxol-5-yl) -4- (3- {3- [6- (ethylamino) pyridin-2-yl] propyl} -1,2,4-trifluoroacetic acid Oxadiazol-5-yl) butanoic acid

  Step 1: 6-Bromo-N-ethylpyridin-2-amine

Example 77 According to the method described in Step 1, iodomethane was replaced with iodoethane to prepare the above compound. This compound was isolated as a pale yellow oil. ¹ HNMR (CD3OD): δ 7.45 (t, 1H), 6.45 (d, 1H), 6.22 (d, 1H), 3.25 (m, 2H), 1.25 (t, 3H).

  Step 2: 4- [6- (Ethylamino) pyridin-2-yl] -butanenitrile

The above compound was prepared according to the method described in Example 77 Step 2. This compound was isolated as a TFA salt. ¹ HNMR (CD ₃ OD): δ 7.45 (t, 1H), 6.45 (d, 1H), 6.22 (d, 1H), 4.5 (m, 1H), 3.25 (m, 2H), 2.72 (t, 2H) , 2.35 (t, 2H), 2.1 (m, 2H), 1.25 (t, 3H).

  Step 3: 4- [6- (Ethylamino) pyridin-2-yl] -N-hydroxybutaneimidamide

The above compound was prepared according to the method described in Example 77 Step 3, using the product of Step 2 of this example. This compound was isolated as a TFA salt. ¹ HNMR (CD ₃ OD): δ 7.55 (m, 1H), 6.55 (m, 2H), 3.45 (m, 2H), 2.72 (t, 2H), 2.35 (t, 2H), 2.1 (m, 2H) , 1.25 (t, 3H).

  Step 4: 3- (3-Fluorophenyl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] propyl-1,2,4-oxadiazole-5-trifluoroacetic acid Yl) butanoic acid

The product from step 3 (336 mg) was dissolved in dioxane (5 mL) containing triethylamine (200 mg) and treated with the appropriate anhydride (210 mg, similar to Example 1) in a scintillation vial at 90 ° C. For 16 hours. The mixture was concentrated to give a crude oil which was purified by reverse phase HPLC (water and 2% TFA / CH ₃ CN mobile phase) to give 0.290 g of the title compound as a TFA salt. ¹ HNMR (CD ₃ OD): 7.85 (m, 1H), 6.92 (d, 1H), 6.78 (s, 1H), 6.68 (m, 3H), 5.87 (s, 2H), 3.62 (m, 1H), 3.45 (q, 2H), 3.25 (m, 2H), 2.75 (m, 6H), 2.10 (m, 2H), 1.35 (t, 3H). Mass spectrum: (MH +): 439.17.

  3- (3-Fluorophenyl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] propyl-1,2,4-oxadiazol-5-yl) butane trifluoroacetate acid

The product from Example 79 Step 3 (336 mg) was dissolved in dioxane (5 mL) containing triethylamine (200 mg), treated with the appropriate anhydride in a scintillation vial and heated at 90 ° C. for 16 hours. The mixture was concentrated to give a crude oil which was purified by reverse phase HPLC (water and 2% TFA / CH ₃ CN mobile phase) to give 0.130 g of the title compound as a TFA salt. ¹ HNMR (CD ₃ OD): δ 7.85 (m, 1H), 7.3 (m, 1H), 7.1 (d, 1H), 7.05 (m, 1H), 6.92 (d, 1H), 6.88 (d, 1H) , 6.68 (d, 2H), 5.87, 3.72 (m, 1H), 3.45 (q, 2H), 3.25 (m, 2H), 2.75 (m, 6H), 2.10 (m, 2H), 1.35 (t, 3H ). Mass spectrum: (MH +): 439.17.

3- (1,3-Benzodioxol-5-yl) -4- (3- {4-[(4-methylpyridin-2-yl) amino] butyl} -1,2,4-oxadiazole -5-yl) butanoic acid
Reaction scheme 20b

  Step 1: Methyl 3- (1,3-benzodioxol-5-yl) -4- [3- (4-oxobutyl) -1,2,4-oxadiazol-5-yl] butanoate:

  Methyl 3- (1,3-benzodioxol-5-yl) -4- [3- (4-hydroxybutyl) -1,2,4-oxadiazol-5-yl] butanoate (previous example A mixture of 2.4 g, 6.5 mmol), N-methylmorpholine-N-oxide (1.1 g, 9.7 mmol), molecular sieve (3.3 g), acetonitrile (20 mL) and dichloromethane (20 mL). And stirred at room temperature. After 10 minutes, tetrapropylammonium perruthenate (0.12 g, 0.32 mmol) was added. The resulting reaction mixture was stirred for 2 h, filtered through a pad of celite (2 ″) and washed with dichloromethane (30 mL). The filtrate was concentrated. The residue was chromatographed (on silica gel, toluene / ethyl acetate = 6: 4) Obtained 1.5 g (60%) of a clear oil whose NMR spectrum was consistent with the proposed structure.

  Step 2: Methyl 3- (1,3-benzodioxol-5-yl) -4- (3- {4-[(4-methylpyridin-2-yl) amino] butyl} -1,2,4 -Oxadiazol-5-yl] butanoate:

The product of step 1 (0.28 g, 0.78 mmol), 2-amino-4-picoline (0.10 g, 0.93 mmol), sodium triacetoxyborohydride (0.26 g, 1.2 mmol) and dichloromethane ( 20 mL) was stirred at room temperature. After 18 hours, the reaction mixture was diluted with ethyl acid (150 mL). The organic layer was washed with H ₂ O (50 mL), brine (50 mL), dried over magnesium sulfate and concentrated. The residue was chromatographed (on silica gel, toluene / ethyl acetate = 85: 15) to give 0.20 g (57%) of a viscous oil. The NMR spectrum was consistent with the proposed structure.

  Step 3: 3- (1,3-Benzodioxol-5-yl) -4- (3- {4-[(4-methylpyridin-2-yl) amino] butyl} -1,2,4- Oxadiazol-5-yl) butanoic acid:

A solution of the product obtained in Step 2 (0.2 g, 0.44 mmol) in sodium hydroxide (15 mL, 1N) was stirred at room temperature. After 18 hours, the reaction was acidified with trifluoroacetic acid (1.5 mL) and concentrated. The residue was purified by HPLC with an acetonitrile gradient of 10-50% in 30 minutes to give 95 mg (37%) of a sticky solid. ¹ H NMR (CDCl ₃ ) δ 9.13 (1H, br.s); 7.61 (1H, d); 6.60-6.66 (3H, m); 6.49-6.52 (2H, m); 5.86 (1H, s); 5.28 (3H, s); 3.63 (1H, m); 3.08-3.25 (4H, m); 2.63-2.79 (4H, m); 1.79 (2H, m); 1.66 (2H, m). C ₂₃ H ₂₆ N ₄ O ₅ 1.25 CF ₃ COOH 0.25 H ₂ O analysis result, calculated value: C 52.31, H 4.78, N 9.57; found value: C 52.01, H 4.78, N 9.53.

  3- (1,3-Benzodioxol-5-yl) -4- (3- {4-[(6-methylpyridin-2-yl) amino] butyl} -1,2,4-oxadiazole -5-yl) butanoic acid:

The above compound was prepared as in Example 81 (using 2-amino-6-picoline instead of 2-amino-4-picoline in step 2). ¹ H NMR (MeOD) δ 7.78 (1H, t, J = 8 Hz); 6.85 (1H, dd, J = 8,2); 6.70 (1H, d, J = 2Hz); 6.68 (2H, dd, J = 8,2Hz); 7.65 (1H, s); 5.85 (2H, s); 3.57-3.64 (1H, m); 3.37 (2H, t, 8Hz); 3.15-3.32 (2H, m); 2.64-2.81 (4H, m); 2.50 (3H, s); 1.76-1.84 (2H, m); 1.62-1.70 (2H, m). C ₂₃ H ₂₆ N ₄ O ₅ 1.6 CF ₃ COOH analysis result, calculated value: C 50.68, H 4.48, N 9.02; Theoretical value: C 50.83, H 4.56, N 8.86.
Reaction scheme 21

  Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- (3- {4-[(4-piperidin-1-ylpyridin-2-yl) amino] butyl} -1,2,4 -Oxadiazol-5-yl) butanoic acid:

  Step 1: Preparation of 4-piperidin-1-ylpyridin-2-amine

4-chloropyridin-2-amine 4-chloropyridin-2-amine (synthesized according to the method outlined in the literature “Sundberg, Richard; Jiang, Songchun; Organic Preparation and Procedure; 29 (1). 1997, 117-122”). : 300 mg, 1.786 mmol) was mixed with piperidine (2.5 mL) in 2 mL of DMA in a sealed container. This mixture was heated in a microwave oven (CSA Discover) at 200 ° C. for 5 minutes. Upon cooling, the reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (eluent, 95: 5: 0.5 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give the product as a yellow solid. It was. Yield: 114 mg (45%). ¹ H NMR (DMSO-d ₆ ) δ 7.63-7.54 (m, 1H), 6.56-6.52 (m, 1H), 6.01-5.96 (m, 1H), 3.50-3.42, (m, 4H), 1.68-1.60 (m, 2H), 1.59-1.50 (m, 4H).

  Step 2: 3- (1,3-Benzodioxol-5-yl) hydrochloride-4- (3- {4-[(4-piperidin-1-ylpyridin-2-yl) amino] butyl} -1, 2,4-oxadiazol-5-yl) butanoic acid

4-Piperidin-1-ylpyridin-2-amine (114 mg, 0.643 mmol) and ethyl (3R) -3- (1,3-benzodioxol-5-yl) -4- [3- (5-oxo A mixture of pentyl) -1,2,4-oxadiazol-5-yl] butanoate (0.578 mmol) was dissolved in CH ₂ Cl ₂ under argon. After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with H ₂ O and extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on reverse phase HPLC (gradient 10-60% CH ₃ CN / H ₂ O / 0.5% HCl) over 30 minutes to give the crude product. This crude product was dissolved in THF (2 mL) at room temperature. 1M LiOH (2.5 mL) was added and stirred at room temperature for 20 hours to continue the reaction. The reaction mixture was acidified with conc. HCl until pH = 1 and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient of 10-50% CH ₃ CN / H ₂ O / 0.5% HCl) over 30 minutes to give the desired product. Yield: 16% over 2 steps. ¹ H NMR (DMSO-d ₆ ) δ 7.60-7.53 (m, 1H), 6.92-6.87 (m, 1H), 6.27-6.22 (m, 1H), 6.65-6.61 (m, 1H), 6.56-6.51 ( m, 1H), 5.97-5.90 (m, 3H), 3.55-3.43 (m, 5H), 3.30-3.13 (m, 4H), 2.77-2.53 (m, 4H), 1.74-1.61 (m, 4H), 1.59-1.47 (m, 6H). C ₂₇ H ₃₃ N ₅ O ₅ 3.4 Analysis result and calculated value of HCl: C, 51.35; H, 5.81; N, 11.09. Found: C, 51.80; H, 6.23; N , 11.07.

  Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- (3- {4-[(4-morpholin-4-ylpyridin-2-yl) amino] butyl} -1,2,4 -Oxadiazol-5-yl) butanoic acid:

According to the method described in Example 83, the above compound was prepared using morpholine instead of piperidine. Yield: 12% over 2 steps. ¹ H NMR (DMSO-d ₆ ) δ 7.67-7.60 (m, 1H), 6.92-6.88 (m, 1H), 6.78-6.75 (m, 1H), 6.67-6.62 (m, 1H), 6.68-6.54 ( m, 1H), 6.02-5.97 (m, 1H), 5.95 (s, 2H), 3.73-3.67 (m, 4H), 3.52-3.38 (m, 5H), 3.31-3.15 (m, 4H), 2.78- 2.54 (m, 4H), 1.74-1.64 (m, 2H), 1.58-1.48 (m, 2H) C ₂₆ H ₃₁ N ₅ O ₆ analysis result, calculated value: 2.4 HCl. C, 52.30; H, 5.64; N, 11.73. Found: C, 52.15; H, 6.25; N, 11.72. Calculated mass: 509.55. Found mass: 510.23 (as MH ⁺ ).

  Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- (3- {4-[(4-thiomorpholin-4-ylpyridin-2-yl) amino] butyl} -1,2, 4-oxadiazol-5-yl) butanoic acid:

The above compound was prepared according to the method described in Example 83, using thiomorpholine instead of piperidine. Yield: 17% over 2 steps. ¹ H NMR (DMSO-d ₆ ) δ 7.58-7.65 (m, 1H), 6.93-6.88 (m, 1H), 6.75-6.72 (m, 1H), 6.65-6.62 (m, 1H), 6.58-6.55 ( m, 1H), 5.98-5.92 (m, 3H), 3.90-3.82 (m, 4H), 3.52-3.41 (m, 1H), 3.32-3.14 (m, 4H), 2.76-2.54 (m, 8H), 1.73-1.64 (m, 2H), 1.57-1.48 (m, 2H). Analytical and calculated values for C ₂₆ H ₃₁ N ₅ O ₅ S: 2.4 HCl: C, 50.93; H, 5.49; N, 11.42. Values: C, 50.93; H, 6.11; N, 11.17. Calculated mass: 525.62. Found mass: 526.21 (for MH ⁺ ).

  Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- [3- (4- {4- (4-methylpiperazin-1-yl) pyridin-2-yl] amino} butyl)- 1,2,4-oxadiazol-5-yl] butanoic acid:

The above compound was prepared according to the method described in Example 83, using N-methylpiperidine instead of piperidine. Yield: 8% over 2 steps. ¹ H NMR (DMSO-d ₆ ) δ 7.77-7.67 (m, 2H), 6.92-6.88 (m, 1H), 6.78-6.74 (m, 1H), 6.67-6.58 (m, 2H), 6.13-6.09 ( m, 1H), 5.95 (s, 1H), 3.58-3.04 (m, 13H), 2.84-2.78 (m, 3H), 2.80-2.55 (m, 4H), 1.75-1.65 (m, 2H), 1.59- 1.50 (m, 2H). C ₂₇ H ₃₄ N ₆ O ₅ analysis, calculated: 3.7 HCl: C, 49.32; H, 5.78; N, 12.78. Found: C, 49.37; H, 6.72; N, 12.29. Calculated mass: 522.60. Found: 523.26 (as MH ⁺ ).

Hydrochloric acid (3S) -3- (1,3-benzodioxol-5-yl) -4- {3- [4- (ethanimidylamino) butyl] -1,2,4-oxadiazole-5 -Il} butanoic acid
Reaction scheme 22

  Step 1: Diethyl 3- (1,3-benzodioxol-5-yl) pentanedioate

To 3- (1,3-benzodioxol-5-yl) pentanedioic acid (3.86 g, 15.3 mol) was added absolute ethanol (19 mL). The reaction mixture was cooled to −10 ° C. and HCl gas was passed through the saturated ethanol reaction mixture between −10 ° C. and 20 ° C. The mixture was then stirred at room temperature for 2 hours resulting in a solution. The solution was concentrated to give 4.79 g of liquid (quantitative yield), which was 97% pure by HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.18 (6H), 2.56 (2H, dd), 2.67 (2H, dd), 3.52-3.62 (1 H, m), 4.15 (4H, double q), 5.92 (2H, s), 6.67-6.72 (3H, m).

  Step 2: (3S) -3- (1,3-benzodioxol-5-yl) -5-ethoxy-5-oxopentanoic acid:

Diethyl 3- (1,3-benzodioxol-5-yl) pentanedioate (4.12 g, 13.4 mol) and 28 mM potassium phosphate buffer (pH 7.4, 120 mL) were mixed with stirring. A suspension was formed. Chirazyme L-2 enzyme (200 mg, 4.85 wt%) was added and the mixture was stirred at room temperature while maintaining the pH at about 7.28 using an automatic titrator. After 24 hours, the same amount of Chillazyme L-2 enzyme (200 mg, 4.85 wt%) was added. The mixture was stirred for a total of 140 hours. During the addition, a total volume of about 20 mL of 1N NaOH solution was automatically added. The reaction mixture is treated with Whatman no.
Filter on 1 filter paper. The filtrate was acidified with 3N HCl (6 mL) and saturated with sodium chloride. Sodium chloride was filtered off and the filtrate was extracted with ethyl acetate (60 mL, 2 times). The ethyl acetate extract was washed with brine (150 mL, twice), dried over sodium sulfate, and then concentrated to give 3.50 g (mass recovery: 93%) of a pale yellow oil. Chiral HPLC analysis indicated that the ratio of the desired enantiomer to the non-target enantiomer was 93: 7 (ie 86% ee). The crude product was further purified by chiral stationary phase chromatography to give a total of 2.86 g of the desired product (yield: 76%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.18 (3H, t), 2.65 (4H, quadruple dd), 3.67 (1 H, quadruple wire), 4.15 (4H, q), 5.91 (2H, s ), 6.70 (3H, m). [Α] ₅₈₉ -6.9 (c 1.017, CHCl ₃ ); [α] ₃₆₅ -29.5 (1.017, CHCl ₃ ).

  Step 3: Ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (tetrahydro-2H-pyran-2-yloxy) butyl] -1,2,4-oxa Diazol-5-yl} butanoate:

  (3S) -3- (1,3-Benzodioxol-5-yl) -5-ethoxy-5-oxopentanoic acid (30.6 g, 104 mmol), CDI (16.9 g, 104 mmol) and DMF (200 mL) ) Was added to 3-N RBF and stirring was continued for 30 minutes under nitrogen. Then (1E) -N′-hydroxy-5- (tetrahydro-2H-pyran-2-yloxy) pentaneimidamide (22.5 g, 104 mmol) is added along with additional DMF (200 mL) and the reaction mixture is stirred for 24 hours. Continued. The reaction mixture was then heated to 90 ° C. Next, DMF was removed and ethyl acetate and water were added. The aqueous layer was washed 3 times with ethyl acetate. Ethyl acetate was concentrated to dryness to give a pure product weighing 40 g (yield: 84%).

  Step 4: 3- (1,3-Benzodioxol-5-yl) -4- [3- (4-hydroxybutyl) -1,2,4-oxadiazol-5-yl] butanoate:

  p-Toluenesulfonic acid (165 mg, 0.87 mmol), ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (tetrahydro-2H-pyran-2-yloxy) Butyl] -1,2,4-oxadiazol-5-yl} butanoate (40 g, 87 mmol) and ethanol (300 mL) were kept stirring for 24 hours. Methylene chloride (300 mL) and PS-DIEA resin (0.921 g, 3.18 mmol) were added and stirring continued for a further 24 hours. The reaction mixture is then passed through filter paper, the solvent is removed, and ethyl 3- (1,3-benzodioxol-5-yl) -4- [3- (4-hydroxybutyl) -1,2, 4-Oxadiazol-5-yl] butanoate (32 g, 85%) was obtained.

  Step 5: Ethyl 3- (1,3-benzodioxol-5-yl) -4- [3- (4-{[(4-methylphenyl) sulfonyl] oxy} butyl) -1,2,4- Oxadiazol-5-yl] butanoate:

  3- (1,3-benzodioxol-5-yl) -4- [3- (4-hydroxybutyl) -1,2,4-oxadiazole-5-methylene chloride (300 mL) Il] butanoate (30 g, 80 mmol) was cooled to 0 ° C. Tosyl chloride (20 g, 104 mmol), DMAP (1 g, 8 mmol) and triethylamine (33 mL, 239 mmol) were then added and the reaction mixture was left in the refrigerator for 36 hours. Since the reaction was not complete, the reaction mixture was kept stirring at room temperature for 18 hours. The solvent was removed. The crude product was passed through a column of silica (eluent, 3: 2 ethyl acetate / hexane). Since not all of the product could be purified on this column, it was passed through another column using a gradient of 5: 1 hexane / ethyl acetate first and finally 1: 1 hexane / ethyl acetate as eluent. . The fractions were collected and ethyl 3- (1,3-benzodioxol-5-yl) -4- [3- (4-{[(4-methylphenyl) sulfonyl] oxy} butyl) -1,2 , 4-oxadiazol-5-yl] butanoate 30.5 g (72%) was obtained.

  Step 6: Ethyl 3- (1,3-benzodioxol-5-yl) -4- (3- {4- [bis (tert-butoxycarbonyl) amino] -butyl} -1,2,4-oxa Diazol-5-yl] butanoate:

  Ethyl 3- (1,3-benzodioxol-5-yl) -4- [3- (4-{[4-methylphenyl) sulfonyl] oxy} butyl) -1,2,4-oxadiazole- 5-yl] butanoate (30.5 g, 57.5 mmol), cesium carbonate (28.1 g, 86 mmol), sodium iodide (0.86 g, 5.75 mmol), di-tert-butyliminodicarboxylate (13. 7 g, 63 mmol) and DMF (300 mL) were stirred at 80 ° C. for 2 h. The reaction mixture was allowed to cool and water and ethyl acetate were added. The aqueous layer was washed 3 times with ethyl acetate. The ethyl acetate fractions were combined and washed with water and brine. The ethyl acetate was then concentrated to dryness and ethyl 3- (1,3-benzodioxol-5-yl) -4- (3- {4- [bis (tert-butoxycarbonyl) amino] butyl} -1 , 2,4-oxadiazol-5-yl) butanoate (29 g, 86%).

  Step 7: Ethyl-4- [3- (4-aminobutyl) -1,2,4-oxadiazol-5-yl] -3- (1,3-benzodioxol-5-yl) butanoate hydrochloride :

  Ethyl 3- (1,3-benzodioxol-5-yl) -4- (3- {4- [bis (tert-butoxycarbonyl) amino] butyl} -1,2,4-oxadiazole-5 -Yl) butanoate (29 g, 50 mmol) was cooled to 5 ° C. Then HCl in ethyl acetate (392.2 mL of a 1.9 M solution) was added. The reaction vessel was capped and the vessel was placed in a refrigerator and left for 18 hours. The reaction mixture was then kept stirring at room temperature for 2 hours. The solvent was removed under steam over nitrogen and the residue was concentrated under vacuum. As a result of the reaction, ethyl-4- [3- (4- (aminobutyl) -1,2,4-oxadiazol-5-yl) -3- (1,3-benzodioxol-5-yl hydrochloride] hydrochloride was obtained. ) 17.5 g (42%) of butanoate was obtained.

  Step 8: Ethyl hydrochloride 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (ethanimidylamino) butyl] -1,2,4-oxadiazole-5 -Il} butanoate:

  Ethyl hydrochloride 4- [3- (4-aminobutyl) -1,2,4-oxadiazol-5-yl] -3- (1,3-benzodioxol-5-yl) butanoate (200 mg, 0 .49 mmol), ethylethaneimidoate (60 mg, 0.49 mmol), triethylamine (0.2 mL, 1.5 mmol) and EtOH (5 mL) were put into a vial, stoppered and kept stirring at 60 ° C. for 6 hours. . The solvent was then removed under nitrogen vapor and purified by reverse phase HPLC. As a result of the reaction, ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (ethanimidylamino) butyl] -1,2,4-oxadiazole- 150 mg (85%) of 5-yl} butanoate were obtained.

  Step 9: 3- (1,3-Benzodioxol-5-yl) hydrochloride-4- {3- [4- (ethanimidylamino) butyl] -1,2,4-oxadiazole-5- Il} butanoic acid

Ethyl hydrochloride 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (ethanimidylamino) butyl] -1,2,4-oxadiazol-5-yl} Butanoate (150 mg, 0.4 mmol), acetone (3 mL), concentrated HCl (0.18 mL, 2.2 mmol) and water (0.18 mL) were kept heated at 57 ° C. for 5 hours. The reaction was then dried under nitrogen vapor and purified by reverse phase HPLC. As a result of the reaction, 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (ethanimidylamino) butyl] -1,2,4-oxadiazole-5 hydrochloride -Yl} butanoic acid 81 mg (52%) was obtained. ¹ H NMR (400MHz) DMSO-d ₆ δ 9.45 (br s, 1H), 9.1 (br s, 1H), 8.55 (br s, 1H), 7.1 (ds, 1H), 6.75 (d, 1H), 6.6 (dd 1H), 5.95 (s, 2H), 3.45 (m, 1H), 3.3-3.1 (m, 4H), 2.7-2.5 (m, 4H), 2.12 (s, 3H), 1.65 (m, 2H) , 1.5 (m, 2H). Mass spectrum: (MH ⁺ ) = 389.2.

Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) butyl] -1, 2,4-oxadiazol-5-yl} butanoic acid:
Reaction scheme 23

Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (ethanimidylamino) butyl] -1,2,4-oxadiazol-5-yl} butane Following the same procedure as described when preparing the acid, using 7-methoxy-3,4,5,6-tetrahydro-2H-azepine and 3- (1,3-benzodioxol-5-HCl hydrochloride Yl) -4- {3- [4- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoic acid. Manufactured. ¹ H NMR (400 MHz) DMSO-d ₆ δ 9.55 (br s, 1H), 9.15 (br s, 1H), 6.9 (ds, 1H), 6.75 (d, 1H), 6.65 (dd, 1H), 5.95 ( s, 2H), 3.55-3.1 (m, 7H), 2.8-2.55 (m, 6H), 1.8-1.5 (m, 10H) Mass spectrum: (MH ⁺ ) = 443.1.

Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (3,4,5,6-tetrahydropyridin-2-ylamino) butyl] -1,2,4 -Oxadiazol-5-yl} butanoic acid:
Reaction scheme 24

  Step 1: 3- (1,3-Benzodioxol-5-yl) hydrochloride-4- {3- [4- (3,4,5,6-tetrahydropyridin-2-ylamino) butyl] -1, 2,4-oxadiazol-5-yl} butanoate:

  Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (ethanimidylamino) butyl] -1,2,4-oxadiazol-5-yl} butane 3- (1,3-benzodioxol-5-yl) hydrochloride using 6-methoxy-2,3,4,5-tetrahydropyridine according to a method similar to that described for preparing the acid -4- {3- [4- (3,4,5,6-tetrahydropyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} butanoate was prepared.

  Step 2: Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (3,4,5,6-tetrahydropyridin-2-ylamino) butyl] -1, 2,4-oxadiazol-5-yl} butanoic acid:

Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (3,4,5,6-tetrahydropyridin-2-ylamino) butyl] -1,2,4 -Oxadiazol-5-yl} butanoate (180 mg, 0.4 mmol), concentrated HCl (0.2 mL, 2.4 mmol), water (0.2 mL, 2.4 mmol) and acetone (1.5 mL) stoppered Placed in vial and continued to stir at room temperature for 18 hours. The solvent was then removed under nitrogen vapor and purified by reverse phase HPLC. As a result of the reaction, hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (3,4,5,6-tetrahydropyridin-2-ylamino) butyl] -1 , 2,4-oxadiazol-5-yl} butanoic acid 92 mg (75%) was obtained. ^{: 1} H NMR (400MHz) DMSO-d ₆ δ 9.55 (br s, 1H), 9.15 (br s, 1H), 6.9 (ds, 1H), 6.75 (d, 1H), 6.65 (dd, 1H), 5.95 (s, 2H), 3.55-3.1 (m, 5H), 2.8-2.55 (m, 6H), 1.8-1.5 (m, 8H) Mass spectrum: (MH ⁺ ) = 429.2.

Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- [3- (4-{[imino (phenyl) methyl] -amino} butyl) -1,2,4-oxadiazole- 5-yl] butanoic acid:
Reaction scheme 25

Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- {3- [4- (3,4,5,6-tetrahydropyridin-2-ylamino) butyl] -1,2,4 -Oxadiazol-5-yl} butanoic acid according to the method described to produce 3- (1,3-benzodioxol-5-yl) -4- [ 3- (4-{[Imino (phenyl) methyl] -amino} butyl) -1,2,4-oxadiazol-5-yl] butanoic acid was prepared. ¹ H NMR (400MHz) DMSO-d ₆ δ 9.65 (br s, 1H), 9.45 (br s, 1H), 9.05 (br s, 1H), 7.73 (m, 3H), 7.6 (m, 2H), 6.9 (sd, 1H), 6.75 (d, 1H), 6.65 (dd, 1H), 5.95 (s, 2H), 3.55-3.1 (m, 5H), 2.8-2.55 (m, 4H), 1.8-1.6 (m , 4H) Mass spectrum: (MH ⁺ ) = 451.1.
Reaction scheme 26

  (2- {6- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] pyridin-3-yl} cyclopropyl) acetic acid:

  Step 1: Synthesis of 2-methoxy-5- (2-methylcyclopropyl) pyridine

A solution of trimethylsulfonium iodide (4.4 g, 0.02 mol) in DMSO (20 mL) was stirred at room temperature. To this solution was added 60% sodium hydride in mineral oil (0.84 g, 0.021 mol) over 20 minutes and the suspension was stirred at room temperature for 1 hour. A solution of 2-methoxy-5-[(1E) -prop-1-enyl] pyridine (2.35 g, 0.01 mol) in DMSO (20 mL) was added dropwise and the reaction mixture was stirred for 3-6 hours. . The reaction was stopped by the addition of saturated NH ₄ Cl, diluted with 4 volumes of water and extracted with CH ₂ Cl ₂ (3 times). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The concentrated residue was purified by chromatography on silica gel with 5% ethyl acetate / hexanes to give 1.5 g (51%) of a white powder. ¹ H NMR (CDCl ₃ ) δ 7.97 (m, 1H), 7.2 (m, 1H), 6.63 (m, 1H), 3.8 (s, 3H), 2.35 (m, 1H), 1.71 (m, 1H), 1.48 (m, 1H), 1.45 (s, 9H), 1.15 (m, 1H).

  Step 2: Synthesis of [2- (6-methoxypyridin-3-yl) cyclopropyl] methanol

To the ester from Step 1 (1.3 mg, 5.2 mmol) in THF (20 mL) at −78 ° C. was added DIBAL (1M in hexane, 48 mL, 13 mmol). The reaction was stirred at −78 ° C. for 30 minutes and then at 0 ° C. for 2-3 hours. The reaction mixture was cooled to −78 ° C., and a saturated aqueous solution of potassium sodium tartrate was gradually added to stop the reaction. The reaction mixture was stirred at room temperature for 2 hours. The solution was extracted with acetate (3 times), washed with brine, dried over sodium sulfate and concentrated to give an oil (0.8 g, 85%). ¹ H NMR (CDCl ₃ ) δ 7.90 (m, 1H), 7.12 (m, 1H), 6.63 (m, 1H), 3.8 (s, 3H), 3.57 (m, 2H), 1.71 (m, 1H), 1.32 (m, 1H), 0.83 (m, 1H).

  Step 3: Synthesis of 2- (6-methoxypyridin-3-yl) cyclopropanecarbaldehyde

A solution of oxalyl chloride (2M in CH ₂ Cl ₂ , 1.67 mL, 3.4 mmol) in methylene chloride (10 mL) was cooled to −78 ° C. under nitrogen and DMSO (10 mL) in DMSO (10 mL). 0.47 mL, 6.7 mmol) solution was added dropwise and stirring was continued for 5 minutes. The product from Step 2 (0.3 g, 1.6 mmol) in CH ₂ Cl ₂ (10 mL) was added dropwise over 5 minutes and the resulting mixture was stirred for 15 minutes at −78 ° C. Triethylamine (1.8 mL, 13 mmol) was added rapidly and stirred at −78 ° C. for an additional 5 minutes followed by 30 minutes at room temperature. The reaction was diluted with water and extracted several times with CH ₂ Cl ₂ . The combined organic extracts were washed with 1.5N aqueous HCl. The aqueous layer after acid extraction was neutralized with 2.5N NaOH and extracted again with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ solution, brine, dried over sodium sulfate and concentrated to give a yellow oil. ¹ H NMR (CDCl ₃ ) δ 9.32 (d, 1H), 7.94 (m, 1H), 7.22 (m, 1H), 6.63 (m, 1H), 3.8 (s, 3H), 2.57 (m, 1H), 2.12 (m, 1H), 1.71 (m, 1H), 1.32 (m, 1H).

  Step 4: Synthesis of [2- (6-methoxypyridin-3-yl) cyclopropyl] acetic acid

To a solution of methoxymethyl (triphenyl) phosphonium chloride (4.5 g, 0.02 mol) in dry THF (25 mL) at 0 ° C. was added lithium bis (trimethylsilyl) amide (1M in THF, 21.5 mL, 0.022 mol) was added. The reaction was stirred at 0 ° C. for 30 minutes. To this solution was added the aldehyde from step 3 (2.31 g, 0.013 mol) in THF (40 mL). After 30 minutes, the ice bath was removed and the reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated. To the resulting methoxyolefin in THF (30 mL) was added HCl (1.5 N, 30 mL) and refluxed for 2 hours. The reaction mixture was cooled to room temperature and neutralized by the addition of a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give an oil that was used without further purification. A solution of aldehyde (6.0 g, 0.032 mol) in ethanol (40 mL) was cooled to 0 ° C. To this solution was added silver nitrate (10.88 g, 0.064 mol in 25 mL distilled water) followed by sodium hydroxide (5.12 g, 0.128 mol in 25 mL distilled water) over 10 minutes. The ice bath was removed after 20 minutes. The black solution was stirred at room temperature for an additional 2 hours, filtered through a pad of celite and washed with excess 2.5N aqueous NaOH. The filtrate was concentrated to remove ethanol. The aqueous solution was extracted with ether followed by ethyl acetate. The combined organic layers were discarded and the aqueous solution was acidified with 5% citric acid. The aqueous layer was extracted with dichloromethane (3 times) and the organic layer was washed with brine, dried over sodium sulfate and concentrated to give 1.5 g of oil. ¹ H NMR (CDCl ₃ ) δ 7.94 (m, 1H), 7.42 (m, 1H), 6.73 (m, 1H), 3.8 (s, 3H), 2.2-2.62 (m, 2H), 1.79 (m, 1H ), 1.2 (m, 1H), 0.92 (m, 1H), 0.85 (m, 1H).

  Step 5: Synthesis of ethyl [2- (6-methoxypyridin-3-yl) cyclopropyl] acetate

To a solution of the acid from step 4 (3 g, 14.5 mmol) in ethanol (30 mL) was added 4N HCl in dioxane (11 mL, 43.4 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give a brown oil. ¹ H NMR (CDCl ₃ ) δ 7.94 (m, 1H), 7.32 (m, 1H), 6.63 (m, 1H), 4.08 (q, 2H), 3.8 (s, 3H), 2.2-2.62 (m, 2H ), 1.73 (m, 1H), 1.24 (t, 3H), 1.2 (m, 1H), 0.92 (m, 1H), 0.85 (m, 1H).

  Step 6: Synthesis of ethyl [2- (6-hydroxypyridin-3-yl) cyclopropyl] acetate

A solution of the methoxyethyl ester from step 5 (1.6 g, 6.8 mmol), sodium iodide (102 g, 0.68 mol) and acetonitrile (200 mL) was cooled to 0 ° C. To this solution, trimethylsilyl chloride (86 mL, 0.68 mol) was added dropwise, followed by additional acetonitrile (100 mL) and water (0.5 mL). The solution was heated at 60 ° C. for 5 hours. The reaction mixture was cooled to 0 ° C. and ethanol (100 mL) was added slowly to quench the reaction. The reaction was stirred at room temperature for 1 hour, the solvent was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with a mixture of brine and Na ₂ S ₂ O ₃ (1: 1). The aqueous layer was extracted with ethyl acetate (4 times). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 1.4 g of white powder. ¹ H NMR (CDCl ₃ ) δ 7.4 (m, 1H), 7.12 (m, 1H), 6.43 (m, 1H), 4.08 (q, 2H), 2.1-2.24 (m, 1H), 2.4-2.6 (m , 1H), 1.63 (m, 1H), 1.14 (m, 1H), 0.92 (m, 1H), 0.85 (m, 1H).

  Step 7: Synthesis of ethyl (2- {6- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] pyridin-3-yl} cyclopropyl) acetate

2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) -1-ethanol (see WO 0033838, 0.211 g, 1.19 mmol) in dry THF (20 mL), A solution of polymer bound PPh3 (0.403 g, 1.19 mmol) was stirred at room temperature. A solution of the cyclopropyl intermediate from step 6 (0.175 g, 0.79 mmol) in dry THF (20 mL) was added, followed by DIAD (0.24 mL, 1.19 mmol) over 5 minutes. . The reaction mixture was stirred at room temperature for 4 days, filtered through celite and washed with excess THF. The solvent was concentrated and the residue was dissolved in 50% acetonitrile in water (10 mL) and acidified by addition of TFA. The residue was purified by reverse phase HPLC to give the title compound as a yellow solid. ¹ H NMR (CD ₃ OD) δ 7.92 (m, 1H), 7.65 (m, 1H), 7.42 (m, 1H), 6.79 (m, 2H), 4.5 (t, 2H), 4.1 (q, 2H) , 3.45 (t, 2H), 3.12 (t, 2H), 2.91 (t, 2H), 2.2-2.4 (m, 1H), 2.5-2.6 (m, 1H), 1.93 (m, 2H), 1.62-1.8 (m, 1H), 1.23 (t, 3H), 0.95 (m, 1H), 0.84 (m, 1H).

  Step 8: Synthesis of (2- {6- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] pyridin-3-yl} cyclopropyl) acetic acid

The ethyl ester from step 7 (0.1 g) was dissolved in ethanol (5 mL) and water (1 mL). LiOH (0.05 g) was added and the reaction was heated at 50 ° C. for 3 hours. The solvent was concentrated to remove ethanol. The residue was dissolved in 50% acetonitrile in water (10 mL) and acidified by addition of TFA. The residue was purified by reverse phase HPLC to give the title compound (0.02 g) as a white solid. ¹ H NMR (CD ₃ OD) δ 7.92 (m, 1H), 7.65 (m, 1H), 7.42 (m, 1H), 6.79 (m, 2H), 4.1 (q, 2H), 3.45 (t, 2H) , 3.12 (t, 2H), 2.91 (t, 2H), 2.2-2.4 (m, 1H), 2.5-2.6 (m, 1H), 1.93 (m, 2H), 1.62-1.8 (m, 1H), 0.95 (m, 1H), 0.84 (m, 1H). Analysis result of C ₂₀ H ₂₃ N ₃ O ₃ , calculated mass: 353.42. Found: 354.1971 (M + H, HRMS).
Reaction scheme 27

  3-Methyl-4- {6- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] pyridin-3-yl} butanoic acid:

  Step 1: Synthesis of ethyl (2E) -3- (6-methoxypyridin-3-yl) -2-methylprop-2-enoate

A solution of 6-methoxynicotine aldehyde (1.0 g, 7.2 mmol) and carboethoxy-ethylidene entry phosphorphosphorane (3.34 g, 9.48 mmol) was dissolved in dichloromethane (70 mL). The solution was refluxed for 3 hours, cooled to room temperature and washed with brine. The aqueous layer was extracted 3 times with dichloromethane and the organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a yellow solid. The residue was chromatographed on silica gel using 20% ethyl acetate / hexanes to give an oil (1.3 g, 80%). NMR (CDCl ₃ ) δ 8.24 (m, 1H), 7.62 (m, 1H), 7.52 (m, 1H), 6.73 (m, 1H), 4.21 (q, 2H), 3.8 (s, 3H), 2.08 ( s, 3H), 1.24 (t, 3H).

  Step 2: Synthesis of ethyl 3- (6-methoxypyridin-3-yl) -2-methylpropanoate

A solution of the olefin from step 1 (1.2 g, 5.4 mmol) was dissolved in ethanol (50 mL) and stirred with 5% Pd / C (0.13 g) at room temperature under a hydrogen atmosphere (30 psi). . After 2 days, the reaction was complete. The catalyst was removed by filtration through celite and washed with 10 mL ethanol. Evaporation and washing of the combined filtrate gave an oil (1.1 g, 91%). NMR (CDCl ₃ ) δ 7.92 (m, 1H), 7.55 (m, 1H), 6.78 (m, 1H), 4.1 (q, 2H), 3.8 (s, 3H), 2.8 (m, 1H), 2.64 ( m, 2H), 1.16 (m, 6H).

  Step 3: Synthesis of 3- (6-methoxypyridin-3-yl) -2-methylpropan-1-ol

To the ester from step 2 (1.3 g, 5.2 mmol) in THF (20 mL) at −78 ° C. was added DIBAL (1M in hexane, 48 mL, 13 mmol). The reaction was stirred at −78 ° C. for 30 minutes and then at 0 ° C. for 2-3 hours. The reaction mixture was cooled to −78 ° C., and a saturated aqueous solution of potassium sodium tartrate was gradually added to stop the reaction. The reaction mixture was stirred at room temperature for 2 hours. The solution was extracted with acetate (3 times), washed with brine, dried over sodium sulfate and concentrated to give an oil (0.8 g, 85%). ¹ H NMR (CDCl ₃ ) δ 7.90 (m, 1H), 7.4 (m, 1H), 6.68 (m, 1H), 3.8 (s, 3H), 3.47 (m, 2H), 2.6-2.7 (m, 1H ), 2.3-2.4 (m, 1H), 0.94 (m, 4H).

  Step 4: Synthesis of 3- (6-methoxypyridin-3-yl) -2-methylpropanal

Of in methylene chloride (30 mL), (2M in _{CH 2 Cl 2, 27mL, 0.054mol} ) oxalyl chloride solution was cooled to -78 ° C. under nitrogen, DMSO for in methylene chloride (30 mL) (7 .6 mL, 0.108 mol) solution was added dropwise and stirring was continued for 5 minutes. The product from Step 3 (4.8 g, 0.027 mol) in CH ₂ Cl ₂ (40 mL) was added dropwise over 5 minutes and the resulting mixture was stirred at −78 ° C. for 15 minutes. Triethylamine (30 mL, 0.216 mol) was added rapidly and the mixture was stirred at −78 ° C. for an additional 5 minutes followed by 30 minutes at room temperature. The reaction was diluted with water and extracted several times with CH ₂ Cl ₂ . The combined organic extracts were washed with 1.5N aqueous HCl. The aqueous layer after acid extraction was neutralized with 2.5N NaOH and extracted again with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ solution, washed with brine, dried over sodium sulfate and concentrated to give a yellow oil (4.6 g). ¹ H NMR (CDCl ₃ ) δ 9.32 (d, 1H), 7.90 (m, 1H), 7.4 (m, 1H), 6.68 (m, 1H), 3.8 (s, 3H), 3.47 (m, 2H), 2.6-2.7 (m, 1H), 2.3-2.4 (m, 1H), 0.94 (m, 4H).

  Step 5: Synthesis of 4- (6-methoxypyridin-3-yl) -3-methylbutanal

  To a solution of methoxymethyl (triphenyl) phosphonium chloride (18.11 g, 0.0528 mol) in dry THF (50 mL) at 0 ° C. was added lithium bis (trimethylsilyl) amide (1M in THF, 58 mL, 0.005 mL). 058 mol) was added. The reaction was stirred at 0 ° C. for 30 minutes. To this solution was added the aldehyde from Step 4 (4.6 g, 0.0264 mol) in THF (50 mL). After 30 minutes, the ice bath was removed and the reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated. To the resulting methoxyolefin in THF (50 mL) was added HCl (1.5 N, 50 mL) and refluxed overnight. The reaction was cooled to room temperature, neutralized by the addition of saturated aqueous sodium bicarbonate and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give an oil that was used without further purification.

  Step 6: Synthesis of 4- (6-methoxypyridin-3-yl) -3-methylbutanoic acid

A solution of the aldehyde from Step 5 (4.0 g, 0.021 mol) in ethanol (30 mL) was cooled to 0 ° C. To this solution was added silver nitrate (6.93 g, 0.042 mol in 25 mL distilled water), followed by sodium hydroxide (3.36 g, 0.084 mol in 25 mL distilled water) over 10 minutes. The ice bath was removed after 20 minutes. The black solution was stirred at room temperature for an additional 2 hours, filtered through a pad of celite and washed with excess 2.5N aqueous NaOH. The filtrate was concentrated to remove ethanol. The aqueous solution was extracted with ether followed by ethyl acetate. The combined organic layers are discarded, the aqueous solution is acidified with 5% citric acid and extracted with dichloromethane (3 times), the combined organic layers are washed with brine, dried over sodium sulfate and concentrated, An oil (3.5 g, 80%) was obtained. ¹ H NMR (CDCl ₃ ) δ 7.9 (m, 1H), 7.4 (m, 1H), 6.68 (m, 1H), 3.8 (s, 3H), 2.52-2.6 (m, 1H), 2.38-2.48 (m , 1H), 2.3-2.35 (m, 1H), 2.1-2.2 (m, 2H), 0.94 (d, 3H).

  Step 7: Synthesis of ethyl 4- (6-methoxypyridin-3-yl) -3-methylbutanoate

To a solution of the acid from step 6 (3.5 g, 14.75 mmol) in ethanol (30 mL) was added 4N HCl in dioxane (11 mL, 43.4 mmol). The reaction mixture was stirred for 3 hours at room temperature. The solvent was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, washed with brine, dried over sodium sulfate and concentrated to give a brown oil. ¹ H NMR (CD ₃ OD) δ 7.92 (m, 1H), 7.65 (m, 1H), 7.42 (m, 1H), 6.79 (m, 2H), 4.5 (t, 2H), 4.1 (q, 2H) , 3.45 (t, 2H), 3.12 (t, 2H), 2.91 (t, 2H), 2.2-2.4 (m, 1H), 2.5-2.6 (m, 1H), 1.93 (m, 2H), 1.62-1.8 (m, 1H), 1.23 (t, 3H), 0.95 (m, 1H), 0.84 (m, 1H).

  Step 8: Synthesis of ethyl 4- (6-hydroxypyridin-3-yl) -3-methylbutanoate

To a solution of the methoxyethyl ester from step 7 (1.5 g, 6.3 mmol) in anhydrous chloroform (20 mL) was added trimethylsilyl iodide (9.0 mL, 63 mmol). The solution was heated at 50 ° C. overnight under a nitrogen atmosphere, cooled to 0 ° C. and quenched with 10 mL of ethanol. The reaction was stirred at room temperature for 1 hour, the solvent was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with a mixture of brine and Na ₂ S ₂ O ₃ (1: 1). The aqueous layer was extracted with ethyl acetate (4 times). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 1.2 g of oil. ¹ H NMR (CDCl ₃ ) δ 7.92 (m, 1H), 7.45 (m, 1H), 6.64 (m, 1H), 4.1 (q, 2H), 2.52-2.6 (m, 1H), 2.38-2.48 (m , 1H), 2.3-2.35 (m, 1H), 2.1-2.2 (m, 2H), 1.1 (t, 3H), 0.94 (d, 3H).

  Step 9: Synthesis of ethyl 3-methyl-4- {6- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] pyridin-3-yl} butanoate

2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) -1-ethanol (see WO 0033838: 1.44 g, 8.07 mmol) in dry THF (40 mL), A solution of polymer bound PPh ₃ (3.26 g, 8.07 mmol) was stirred at room temperature. A solution of the compound from step 8 (1.2 g, 5.38 mmol) in dry THF (40 mL) was added followed by DIAD (1.76 mL, 8.07 mmol) over 15 min. The reaction mixture was stirred at room temperature overnight, filtered through celite and washed with excess THF. The solvent was concentrated and the residue was dissolved in 50% acetonitrile in water (10 mL) and acidified by addition of TFA. The residue was purified by reverse phase HPLC to give the title compound as a white solid. ¹ H NMR (CD ₃ OD) δ 7.62 (m, 1H), 7.45 (m, 1H), 7.36 (m, 1H), 6.4-6.5 (m, 2H), 4.3 (t, 2H), 4.1 (q, 2H), 3.5 (t, 2H), 3.2 (t, 2H), 2.72 (t, 2H), 2.4 (m, 1H), 2.2-2.4 (m, 2H), 2.0-2.2 (m, 2H), 1.93 (m, 2H), 1.2 (t, 3H), 0.9 (d, 3H).

  Step 10: Synthesis of 3-methyl-4- {6- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] pyridin-3-yl} butanoic acid

The ethyl ester from step 9 (1.0 g) was dissolved in ethanol (10 mL) and water (1 mL). LiOH (0.21 g) was added and the reaction was heated at 50 ° C. for 3 hours. The solvent was concentrated to remove ethanol. The residue was dissolved in 50% acetonitrile in water (10 mL) and acidified by addition of TFA. The residue was purified by reverse phase HPLC to give the title compound as a white solid (0.22 g). ¹ H NMR (CD ₃ OD) δ 7.64 (m, 1H), 7.46 (m, 1H), 7.38 (m, 1H), 6.4-6.5 (m, 2H), 4.3 (t, 2H), 3.5 (t, 2H), 3.2 (t, 2H), 2.72 (t, 2H), 2.4 (m, 1H), 2.2-2.4 (m, 2H), 2.0-2.2 (m, 2H), 1.93 (m, 2H), 0.9 _{. (d, 3H) C 20} H 25 mass N ₃ O _3, calculated:. 355.43 Found: 356.1973 (M + H, HRMS ).
Reaction scheme 28

  3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl trifluoroacetate ] -1,3,4-oxadiazol-2-yl} butanoic acid

  Step 1: Preparation of 4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanoic acid

A flask containing 4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanenitrile (800 mg, 3.97 mmol) was cooled to 0 ° C. Concentrated HCl (25 mL) was added slowly, warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated in vacuo and lyophilized. The yield was quantitative and esterification proceeded immediately. ¹ H NMR (DMSO-d ₆ ) δ 7.61 (d, 1H), 6.60 (d, 1H), 3.45-3.36 (m, 2H), 2.74 (t, 2H), 2.65 (t, 2H), 2.08 (t , 2H), 1.88-1.78 (m, 4H).

  Step 2: Preparation of ethyl 4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanoate

A mixture of 4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanoic acid (0.80 g, 3.97 mmol) in HCl / EtOH solution (25 mL) was heated. , Refluxed for 16 hours. The reaction was concentrated in vacuo and purified by reverse phase HPLC with a gradient of 5-40% acetonitrile / H ₂ O / 2% TFA over 30 minutes to give a yellow solid. Yield: 350 mg (as TFA salt) (24% over 2 steps). ¹ H NMR (DMSO-d ₆ ) δ 7.60 (d, 1H), 6.60 (d, 1H), 4.04 (q, 2H), 3.45-3.36 (m, 2H), 2.75 (t, 2H), 2.66 (t , 2H), 2.33 (t, 2H), 1.93-1.78 (m, 4H), 1.16 (t, 3H).

  Step 3: Preparation of 4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanohydrazide

Ethyl 4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanoate (300 mg, 0.83 mmol) was dissolved in hydrazine hydrate (neat) and 100 Heat at 4 ° C. for 4 hours. The reaction was cooled and concentrated in vacuo to give 305 mg of the desired crude product as a sticky white solid. ¹ H NMR (DMSO-d ₆ ) δ 7.33 (d, 1H), 6.42, (d, 1H), 3.03 (t, 2H), 2.67 (t, 2H), 2.55-2.48 (m, 2H), 2.04 ( t, 2H), 1.88-1.73 (m, 4H).

  Step 4: Trifluoroacetic acid 3- (1,3-benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,3,4-oxadiazol-2-yl} butanoic acid

4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanohydrazide (305 mg) and anhydride, 4- (1,3-benzodioxol-5-yl) dihydro -2H-pyran-2,6 (3H) -dione (334.8 mg) was dissolved in 1,4-dioxane under argon. Heated at 100 ° C. for 16 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was purified by reverse phase HPLC with a gradient of 10-50% acetonitrile / H ₂ O / 2% TFA over 30 minutes to give a white solid. Yield: 153 mg (19%). ¹ H NMR (DMSO-d ₆ ) δ 7.65-7.60 (d, 1H), 7.10-7.00 (m, 1H), 6.90-6.79 (m, 2H), 6.67-6.61 (m, 1H), 6.12-5.97 ( m, 2H), 3.45-3.38 (m, 2H), 3.16-2.99 (m, 2H), 2.94-2.83 (2H), 2.77-2.65 (m, 4H), 2.33-2.24 (m, 2H), 1.95- 1.77 (m, 4H). C ₂₄ H ₂₆ N ₄ O ₅ 1.4 TFA analysis, calculated: C, 52.76; H, 4.53; N, 9.18. Found: C, 52.59; H, 4.80; N, 9.29. Calculated mass: 450.50. Found: 451.0 (MH ⁺ As).
Reaction scheme 29

  3- (3-Fluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3,4-trifluoroacetic acid Production of oxadiazol-2-yl} butanoic acid.

  Step 1: Preparation of ethyl 4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanoate

Ethyl 4- (1,8-naphthyridin-2-yl) butanoate (5.45 g) was hydrogenated in ethanol with 20% Pd (OH) ₂ / C at 5 psi at room temperature for 6 hours. The reaction was filtered and concentrated in vacuo to give the desired crude product as a yellow oil. Yield: 5.12 g (92%). ¹ H NMR (DMSO-d ₆ ) δ 7.02 (d, 1H), 6.22 (d, 1H), 4.05 (q, 2H), 3.25-3.20 (m, 2H), 2.59 (t, 2H), 2.44 (t , 2H), 2.25 (t, 2H), 1.87-1.80 (m, 2H), 1.79-1.71 (m, 2H), 1.17 (t, 3H).

  Step 2: 3- (3-Fluorophenyl) -5-oxo-5- {2- [4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanoyl] hydrazino}- Production of pentanoic acid

  4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanohydrazide (prepared as in Reaction Scheme 29: 510 mg, 2.18 mmol) and anhydrous 4- (3- A mixture of fluorophenyl) dihydro-2H-pyran-2,6 (3H) -dione (500 mg, 2.40 mmol) was mixed in 1,4-dioxane and heated at 70 ° C. for 16 hours. The resulting mixture was cooled and concentrated in vacuo to give the desired crude beige solid.

¹ H NMR (DMSO-d ₆ ) δ 7.35-7.25 (m, 1H), 7.12-6.95 (m, 4H), 6.28-6.21 (m, 1H), 3.55-3.43 (m, 1H), 3.28-3.18 ( m, 2 H), 2.78-2.38 (m, 8 H), 2.13-2.04 (t, 2 H), 1.75-1.69 (m, 4H).

  Step 3: Tri (3-fluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3 trifluoroacetic acid , 4-oxadiazol-2-yl} butanoic acid

3- (3-Fluorophenyl) -5-oxo-5- {2- [4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanoyl] hydrazino} -pentanoic acid ( 200 mg, 0.45 mmol) was dissolved in AcOH (3 mL) in a stoppered test tube. The reaction mixture was heated at 85 ° C. for 20 hours. The reaction was cooled and concentrated in vacuo. The residue was purified by reverse phase HPLC with a gradient of 5-40% acetonitrile / H ₂ O / 2% TFA over 30 minutes to give a yellow solid. Yield: 81 mg (32%). ¹ H NMR (DMSO-d ₆ ) δ 7.65-7.60 (m, 1H), 7.48 -7.21 (m, 3H), 7.15-7.05 (m, 1H), 6.65-6.60 (m, 1H), 3.55-3.38 ( m, 3H), 3.24-3.07 (m, 2H), 3.03-2.92 (m, 2H), 2.79-2.68 (m, 4H), 3.34-2.25 (t, 2H), 1.95-1.68 (m, 4H). , C ₂₃ H ₂₅ FN ₄ O ₃ 1.2 TFA, 1.2 Analysis of H ₂ O, Calculated: C, 54.18; H, 4.73; N, 9.95. Measured: C, 53.96; H, 4.85; N, 10.17. Calculated: 424.47. Measured: 425.14 ( As MH ⁺ ).

  3- (3-Fluoro-4-methoxyphenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, trifluoroacetic acid, 3,4-oxadiazol-2-yl} butanoic acid:

Starting from 4- (3-fluoro-4-methoxyphenyl) -dihydro-2H-pyran-2,6 (3H) -dione, the above compound was prepared by the method described in steps 2 and 3 of Example 94. Manufactured. ¹ H NMR (DMSO-d ₆ ) δ 7.67-7.60 (m, 1H), 7.27-.17 (m, 1H), 7.11-7.08 (m, 2H), 6.68-6.60 (m, 1H), 3.83 (s , 1H), 3.47-3.38 (m, 3H), 3.18-3.01 (m, 2H), 2.98-2.89 (m, 2H), 2.78-2.65 (m, 4H), 2.33-2.25 (m, 2H), 1.92 ^{.. -1.78 (m, 4H)} , C 24 H 27 FN 4 O 4 2.5 TFA analysis of calculated values:. C, 47.10; H, 4.02; N, 7.58 Found: C, 47.22; H, 4.06 ; N, 7.60. Calculated mass: 454.49. Found: 455.14 (as MH ⁺ ).

  3- (3,5-Dimethoxyphenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3, trifluoroacetic acid 4-oxadiazol-2-yl} butanoic acid:

The above compound was prepared using a method similar to that described in Example 94, starting from 4- (3,5-dimethoxyphenyl) -dihydro-2H-pyran-2,6 (3H) -dione. ¹ H NMR (DMSO-d ₆ ) δ 7.65-7.59 (m, 1H), 6.68-6.53 (m, 3H), 6.42-6.35 (m, 1H), 3.73 (s, 6H), 3.45-3.38 (m, 3H), 3.19-3.05 (m, 2H), 2.98-2.85 (m, 2H), 2.34-2.24 (m, 2H), 1.95-1.78 (m, 4H), C ₂₅ H ₃₀ N ₄ O ₅ 1.5 TFA analysis result, calculated value: C, 52.75; H, 4.98; N, 8.79. Actual value: C, 52.60; H, 5.40; N, 8.85. Calculated mass: 466.53. Actual value: 467.00 (MH ^{As +} ).

  3- (2-Methyl-1,3-thiazol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) trifluoroacetic acid Propyl] -1,3,4-oxadiazol-2-yl} butanoic acid:

Starting from 4- (2-methyl-1,3-thiazol-5-yl) -dihydro-2H-pyran-2,6 (3H) -dione, a method similar to that described in Example 94 described above was used. The compound was prepared. ¹ H NMR (DMSO-d ₆ ) δ 7.65-7.48 (m, 2H), 6.65-6.58 (m, 1H), 3.90-3.70 (m, 1H), 3.47-3.39 (m, 2H), 3.22-2.98 ( m, 4H), 2.78-2.65 (m , 4H), 2.62 (s, 3H), 2.32-2.22 (m, 2H), 1.94-1.75 (m, 4H), C 21 H 25 N 5 O 3 S. 3.2 Calculated value of TFA .: Calculated value: C, 41.53; H, 3.59; N, 8.84. Measured value: C, 41.46; H, 3.97; N, 9.12. Calculated value of mass: 427.52. Found: 428.00 (MH ⁺ As).

  3- (4-Fluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3,4-trifluoroacetic acid Oxadiazol-2-yl} butanoic acid:

The above compound was prepared using a method similar to that described in Example 94, starting from 4- (4-fluorophenyl) -dihydro-2H-pyran-2,6 (3H) -dione.
¹ H NMR (DMSO-d ₆ ) δ 7.65 -7.59 (m, 1H), 7.50-7.39 (m, 2H), 7.25-7.12 (m, 2H), 3.62-3.38 (m, 3H), 3.20-3.04 ( m, 2H), 3.00-2.88 (m, 2H), 2.78-2.65 (m, 4H), 2.35-2.25 (m, 2H), 1.97-1.67 (m, 4H), C ₂₃ H ₂₅ FN ₄ O ₃ 1.9TFA. Analytical result, calculated value: C, 50.21; H, 4.23; N, 8.74. Found value: C, 50.49; H, 4.64; N, 8.32. Calculated mass: 424.47. Found value: 425.14 (MH ^{As +} ).

  3- (3,5-Difluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3, trifluoroacetic acid 4-oxadiazol-2-yl} butanoic acid:

The above compound was prepared using a method similar to that described in Example 94, starting from 4- (3,5-difluorophenyl) dihydro-2H-pyran-2,6 (3H) -dione. ¹ H NMR (DMSO-d ₆ ) δ 7.65-7.58- (m, 1H), 7.25-7.10 (m, 3H), 6.67-6.61 (m, 1H), 3.54-3.38 (m, 3H), 3.22-3.06 (m, 2H), 3.04-2.93 (m, 2H), 2.78-2.68 (m, 4H), 2.34-2.25 (m, 2H), 1.95-1.78 (m, 4H). C ₂₃ H ₂₄ F ₂ N ₄ O ₃ 1.5 TFA. Analysis, calculated values: C, 50.90; H, 4.19; N, 9.13. Measured values: C, 50.08; H, 4.54; N, 8.51. Calculated mass: 442.46. Measured values: 443.07 (MH ^{As +} ).

  3- (3,5-Difluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3, trifluoroacetic acid 4-thiadiazol-2-yl} butanoic acid:

3- (3,5-Difluorophenyl) -5-oxo-5- {2- [4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanoyl] hydrazino} pentanoic acid A mixture of (992 mg, 2.24 mmol) was stirred in benzene (10 mL) under argon. P ₂ S ₅ (1.60 g, 3.60 mmol) was added and heated to reflux for 16 hours. The reaction mixture was concentrated in vacuo and triturated with an acetonitrile / H ₂ O mixture. The supernatant was decanted and concentrated in vacuo. This process was repeated several times and the resulting residue was dissolved in AcOH (25 mL) and heated to reflux overnight. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC with a gradient of 10-50% acetonitrile / H ₂ O / 2% NH ₄ OAC over 30 minutes. To obtain the TFA salt of the desired product, it was purified once more by reverse phase HPLC with another gradient of 10-50% acetonitrile / H ₂ O / 0.05% TFA over 30 minutes. Yield: 80 mg (6%). ¹ H NMR (DMSO-d ₆ ) δ 7.61-7.52 (m, 1H), 7.07-6.98 (m, 3H), 6.59-6.53 (m, 1H), 3.52-3.32 (m, 5H), 3.04-2.95 ( m, 2H), 2.79-2.58 (m, 4H), 2.03-1.93 (m, 2H), 1.84-1.74 (m, 2H). C ₂₃ H ₂₄ F ₂ N ₄ O ₂ S 2.5 TFA analysis, calculated values: C, 45.23; H, 3.59; N, 7.53. Measured values: C, 45.33; H, 3.72; N, 8.01. Calculated mass: 458.53. Measured values: 459.16 (MH ^{As +} ).

  3- (4-Fluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3,4-trifluoroacetic acid Thiadiazol-2-yl} butanoic acid:

3- (4-Fluorophenyl) -5-oxo-5- {2- [4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanoyl] hydrazino} pentanoic acid (992 mg The above compound was prepared using the method described in Example 100, starting from 2.24 mmol). ¹ H NMR (DMSO-d ₆ ) δ 7.54 -7.48 (m, 1H), 7.24-7.15 (m, 2H), 7.06-6.94 (m, 2H), 6.52-6.45 (m, 1H), 2.42-3.24 ( m, 5H), 2.95-2.88 (m, 2H), 2.74-2.47 (m, 6H), 1.97-1.83 (m, 2H), 1.78-1.67 (m, 2H). C ₂₃ H ₂₅ FN ₄ O ₂ S 1.7 TFA analysis result, calculated value: C, 49.98; H, 4.24; N, 8.83. Actual value: C, 49.83; H, 4.52; N, 9.21. Mass, calculated value: 440.53. Actual value: 441.17 (MH ^{As +} ).

  3- (2-Methyl-1,3-thiazol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) trifluoroacetic acid Propyl] -1,3,4-thiadiazol-2-yl} butanoic acid:

3- (2-Methyl-1,3-thiazol-5-yl) -5-oxo-5- {2- [4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) The above compound was prepared using the method described in Example 100 starting from) butanoyl] hydrazino} pentanoic acid (992 mg, 2.24 mmol). ¹ H NMR (DMSO-d ₆ ) δ 7.68-7.62 (m, 1H), 6.69-6.63 (m, 1H), 3.90-3.77 (m, 1H), 3.59-3.38 (m, 2H), 3.15-3.07 ( m, 2H), 2.91-2.63 (m, 8H), 2.62 (s, 3H), 2.15-2.02 (m, 2H), 1.94 -1.83 (m, 2H). C ₂₁ H ₂₅ N ₅ O ₂ S ₂ 4.5 TFA analysis, calculated values: C, 37.66; H, 3.11; N, 7.32.Observed values: C, 37.66; H, 3.73; N, 9.56. Mass, calculated values: 443.59.Observed values: 444.15 (MH ⁺ As).

  3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl trifluoroacetate ] -1,3,4-thiadiazol-2-yl} butanoic acid:

3- (1,3-Benzodioxol-5-yl) -5-oxo-5- {2- [4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) The above compound was prepared using the method described in Example 100 starting from butanoyl] hydrazino} pentanoic acid (992 mg, 2.24 mmol). ¹ H NMR (DMSO-d ₆ ) δ 8.00 (br s, 1H), 7.60 (d, 1H), 6.93 (d, 1H), 6.77 (d, 1H), 6.67 (dd, 1H), 6.57 (d, 1H), 5.94 (d, 2H), 3.43-3.30 (m, 4H), 3.02 (t, 2H), 2.77-2.66- (m, 4H), 2.60-2.45 (m, 2H), 2.04-1.95 (m , 2H), 1.87-1.78 (m, 2H). Mass, calculated: 467.1746. Found: 467.1745 (as MH ⁺ ).

3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] isoxazole- Synthesis of 5-yl} butanoic acid
Reaction scheme 30

  Step 1: Synthesis of 2-methyl-1,8-naphthyridine

To 2-amino-3-nicotinaldehyde (50.0 g, 0.41 mol) in EtOH (600 mL) was added L-proline (51 g, 0.45 mol) and acetone (90 mL, 1.23 mol). The reaction mixture was stirred overnight. The reaction mixture was cooled to room temperature and the white solid was filtered off. The filtrate was concentrated to yield a yellow solid, redissolved in CH ₂ Cl ₂ (500 mL) and the insoluble material was filtered off. The filtrate was washed with water (100 mL, 2 times), the organic layer was separated, the aqueous layers were combined and washed with CH ₂ Cl ₂ (75 mL, 4 times). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated to a yellow solid (57.2 g, 0.40 mol, 97%).

  Step 2: Synthesis of (E) -1-ethoxy-2- (1,8-naphthyridin-2-yl) ethanol

The product from step 1 (81.5 g, 0.57 mol) in anhydrous THF (1.9 L) under Ar gas at −40 ° C. was added to lithium bis (trimethylsilyl) amide (1M in THF, 1.2 L, 1.2 mol) was added. After stirring at −40 ° C. for 30 minutes, diethyl carbonate (72.5 mL, 0.60 mol) was added. The reaction mixture was warmed to 0 ° C. and stirred for 2 hours. The reaction mixture was quenched into saturated aqueous NH ₄ Cl (700 mL) and THF was removed under reduced pressure. The resulting mixture was extracted with EtOAc (700 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 50% EtOAc / hexanes to give a yellow solid (81.2 g, 0.38 mol, 66%). ¹ H NMR (400 MHz, DMSO-d6) δ 1.22 (t, 3H), 4.11 (q, 2H), 4.89 (s, 1H), 6.78 (d, 1H), 7.15 (dd, 1H), 7.47 (d , 1H), 7.80 (d, 1H), 8.36 (d, 1H), 11.8 (bs, 1H). LC-MS (MH +) = 217.

  Step 3: Synthesis of ethyl 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl acetate

The compound from step 2 (51.4 g, 0.24 mol) in EtOH was hydrogenated with 20% Pd (OH) ₂ / C at room temperature under a pressure of 5 psi. After 2 hours, the reaction was complete. Pd (OH) ₂ / C was filtered off and the filtrate was concentrated to give a yellow solid (50.3 g, 0.23 mol, 96%). ¹ H NMR (400 MHz, DMSO-d6) δ 1.17 (t, 3H), 1.74 (m, 2H), 2.61 (t, 2H), (3.23, 2H), 3.47 (s, 2H), 4.04 (q, 2H), 6.32 (d, 1H), 6.41 (bs, 1H), 7.07 (d, 1H). LC-MS (MH +) = 221.

  Step 4: Synthesis of 2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethanol

To anhydrous THF (910 mL) under Ar gas at room temperature was added a 1M solution of lithium aluminum hydride in THF (910 mL, 0.91 mol). The temperature of the reaction mixture was lowered to 15 ° C. and a solution of the product from Step 3 (50.3 g, 0.23 mol) in anhydrous THF (500 mL) was added slowly over 30 minutes. The resulting reaction was stirred at room temperature for 3.5 hours. The temperature was lowered to 0 ° C. and the reaction was quenched slowly with brine (260 mL). While the reaction was stopped, the emulsion was broken down by adding additional THF (300 mL). After all the brine was added, the reaction mixture was stirred overnight at room temperature. Sodium sulfate was added and the mixture was stirred for 15 minutes and filtered. The residue was washed with EtOAc (300 mL, 3 times). The organic layers were combined and concentrated to about 1.5 L, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 100% EtOAc followed by 5% MtOH / EtOAc as eluent. The desired product was obtained as a solid (34.9 g, 85%).
Reaction scheme 31

  Step 5: Synthesis of 3- (1,3-benzodioxol-5-yl) -7-ethoxy-5,7-dioxoheptanoic acid

To a solution of anhydrous EtOAc (4.38 mL, 44.8 mmol) in anhydrous THF (25 mL) under Ar gas at −78 ° C. was added lithium diisopropylamide (2M in heptane / THF / ethylbenzene, 22.4 mL, 44.8 mmol) was added slowly. The resulting solution was stirred at −78 ° C. for 25 minutes and added dropwise to a solution of anhydride (5.0 g, 21.3 mmol) in anhydrous THF (170 mL) via cannula at −78 ° C. under Ar gas. The reaction mixture was stirred at −78 ° C. for 1.5 hours. The reaction was quenched with 2N HCl in ether (80 mL) and allowed to warm to room temperature. To the reaction mixture was added water (100 mL) and extracted with EtOAc (100 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 40% EtOAc / hexanes to give a white solid (5.61 g, 17.4 mmol, 82%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.25 (t, 3H), 2.55-2.73 (m, 2H), 2.90 (m, 2H), 3.34 (s, 2H), 3.60 (m, 1H), 4.15 ( q, 2H), 5.93 (s, 2H), 6.70 (m, 3H). LC-MS (M + Na) = 345.

  Step 6: Synthesis of ethyl 3- (1,3-benzodioxol-5-yl) -4- (3-hydroxyisoxazol-5-yl) butanoate

Hydroxylamine hydrochloride (1.1 g, 16.4 mmol) was dissolved in about 4.3 mL of 2N NaOH to give a solution of pH 10.0 ± 0.3 (using a pH meter). While cooling this solution to 0 ° C. and stirring vigorously, a solution of the product from step 5 (4.8 g, 14.9 mmol) in 2N NaOH (ca. 8.5 mL) was added slowly, during which time 2N NaOH was added. The pH of the reaction mixture was kept at 10.0 ± 0.3 by dropwise addition. After complete addition, the reaction mixture was stirred at 0 ° C. for 1.5 hours and quenched into ice-cold concentrated HCl (20 mL). The reaction mixture was warmed to room temperature and stirred for 4 hours. The resulting mixture was poured into ice water (200 mL) and extracted with EtOAc (200 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue (3.8 g) was dissolved in EtOH (15 mL) and 4N HCl in dioxane (15 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography using 50% EtOAc / hexane as eluent. A yellow oil (1.22 g, 3.8 mmol, 26%) was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 1.08 (t, 3H), 2.54-2.72 (m, 2H), 2.93 (m, 2H), 3.33 (m, 1H), 3.95 (q, 2H), 5.58 (s, 1H), 5.97 (s, 2H). 6.68 (dd, 1H), 6.78 (d, 1H), 6.91 (d, 1H), 10.95 (s, 1H). LC-MS (MH +) = 320.

  Step 7: Ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Synthesis of [Ethoxy] isoxazol-5-yl} butanoate

2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethanol (400 mg, 1.2 mmol), ethyl 3- () in anhydrous THF under Ar gas at room temperature. 1,3-benzodioxol-5-yl) -4- (3-hydroxyisoxazol-5-yl) butanoate (246 mg, 1.4 mmol) and triphenylphosphine (393 mg, 1.5 mmol) were added to diethyl Azodicarboxylate (236 μL, 1.5 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was quenched into saturated aqueous NH ₄ Cl (5 mL) and extracted with EtOAc (5 mL, 3 ×). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residual oil was purified by flash column chromatography using 100% EtOAc as eluent. An oil (466 mg) containing the desired product and impurities of triphenylphosphine oxide was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 1.06 (t, 3H), 1.75 (m, 2H), 2.53-2.73 (m, 4H), 2.84 (t, 2H), 2.97 (m, 2H), 3.23 (m, 2H), 3.35 (m, 1H), 3.94 (m, 2H), 4.35 (t, 2H), 5.79 (s, 1H), 5.97 (s, 2H), 6.29 (d, 1H), 6.34 ( bs, 1H), 6.68 (dd, 1H), 6.77 (d, 1H), 6.91 (d, 1H), 7.03 (d, 1H). LC-MS (MH +) = 480.

  Step 8: 3- (1,3-benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy Synthesis of isoxazol-5-yl} butanoic acid

To the impure product from step 7 (466 mg) in THF (5 mL) was added 1 N NaOH (5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified, concentrated and purified by flash column chromatography using (H ₂ O / TFA) / CH ₃ CN ( _2.5 mL TFA in H ₂ O 4 L) as eluent. A white solid (141, 0.24 mmol, yield over 2 steps: 19%) was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 1.82 (m, 2H), 2.45-2.64 (m, 2H), 2.74 (t, 2H), 2.97 (m, 2H), 3.08 (t, 2H), 3.30 (m, 1H), 3.40 (m, 2H), 4.38 (t, 2H), 5.81 (s, 1H), 5.96 (s, 2H), 6.65 (m, 2H), 6.77 (d, 1H), 6.90 ( d, 1H), 7.58 (d , 1H), 8.07 (bs, 1H), 12.14 (bs, 1H). LC-MS (MH +) = 451. C 24 H 25 N 3 O 6. 1.2TFA. 0.25H 2 Analysis result of O, calculated value: C 53.49 H 4.54 N 7.09. Found: C 53.37 H 4.40 N 7.07.
Reaction scheme 32

  3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -2H -Synthesis of tetraazol-2-yl} butanoic acid.

  Step 1: Synthesis of 1- (1,3-benzodioxol-5-yl) -2-bromoethanone

3 ′, 4 ′-(methylenedioxy) acetophenone (10.0 g, 61 mmol) in CHCl ₃ (360 mL) was added Cu (II) Br ₂ (27.0 g, 122 mmol) in EtOAc (360 mL). To the mixture at 65 ° C. The resulting mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and Norite was added. The mixture was stirred for 1 hour and filtered through celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 15% EtOAc / hexane as eluent. A white solid (8.44 g, 57%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 4.85 (s, 2H), 6.15 (s, 2H), 7.07 (d, 1H), 7.47 (d, 1H), 7.65 (dd, 1 H). LC-MS (MH +) = 244.

  Step 2: Synthesis of 2- [3- (2H-tetraazol-5-yl) propyl] -1,8-naphthyridine

Nitrile (previously synthesized: 1.0 g, 5.1 mmol) in 1-methyl-2-pyrrolidinone (15 mL) was added to NaN ₃ (1.0 g, 15 mmol) and Et ₃ NHCl (1.1 g, 8.1 mmol). ) Was added. The reaction mixture was heated at 160 ° C. for 8 hours and allowed to cool to room temperature overnight. The precipitate was filtered. To the filtrate was added 2N HCl in ether (70 mL). After stirring for 30 minutes, the resulting brown solid was filtered and washed with EtOAc (5 mL, 3 times) and CH ₂ Cl ₂ (5 mL, 3 times). A brown solid (1.26 g, 4.0 mmol, 79%) was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 2.32 (m, 2H), 3.04 (t, 2H), 3.24 (t, 2H), 8.0 (m, 2H), 8.87 (d, 1H), 9.0 (dd , 1H), 9.30 (dd, 1H) LC-MS (MH +) = 241. C 12 H 12 N 6 2HCl analysis of calculated ^{values:.. C 46.02 H 4.51 N} 26.83 Found:. C 45.76 H 4.23 N 26.60.

  Step 3: 1- (1,3-Benzodioxol-5-yl) -2- {5- [3- (1,8-naphthyridin-2-yl) propyl] -2H-tetraazol-2-yl } Ethanone and 1- (1,3-benzodioxol-5-yl) -2- {5- [3- (1,8-naphthyridin-2-yl) propyl] -1H-tetraazole-1- Yle} ethanone synthesis

At room temperature, 2- [3- (2H-tetraazol-5-yl) propyl] -1,8-naphthyridine (918 mg, 3.6 mmol) in anhydrous CH ₂ Cl ₂ (35 mL) was added to anhydrous Et ₃ N. (5 mL, 36 mmol) was added. After 45 minutes at room temperature, compound 1- (1,3-benzodioxol-5-yl) -2-bromoethanone (1.1 g, 4.4 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 5% MeOH / EtOAc as eluent. Isomer A (400 mg, 1.0 mmol, 28%) and isomer B (488 mg, 1.2 mmol, 34%) were obtained. Compound A: ¹ H NMR (400 MHz, DMSO-d6) δ 2.28 (m, 2H), 3.00 (t, 2H), 3.07 (t, 2H), 6.19 (s, 2H), 6.49 (s, 2H), 7.15 (d, 1H), 7.52 (d, 1H), 7.57 (m, 2H), 7.73 (dd, 1H), 8.40 (d, 1H), 8.44 (dd, 1H), 9.03 (dd, 1H). LC -MS (MH +) = 403. Compound B: ¹ H NMR (400 MHz, DMSO-d6) δ 2.24 (m, 2H), 2.91 (t, 2H), 3.05 (t, 2H), 6.19 (s, 2H) , 6.33 (s, 2H), 7.14 (d, 1H), 7.50 (d, 1H), 7.54 (d, 1H), 7.58 (dd, 1H), 7.73 (dd, 1H), 8.35 (d, 1H), 8.41 (dd, 1H), 9.02 (dd, 1H). LC-MS (MH +) = 403.

  Step 4: Ethyl (2E) -3- (1,3-benzodioxol-5-yl) -4- {5- [3- (1,8-naphthyridin-2-yl) propyl] -2H-tetra Synthesis of Azol-2-yl} but-2-enoate

To a solution of t-BuOK (1M in THF, 1.4 mL, 1.4 mmol) in anhydrous CH ₂ Cl ₂ (6 mL) at room temperature under Ar gas, triethylphosphonoacetate (277 μL, 1.4 mmol) was added. Added. After stirring for 30 minutes, 1- (1,3-benzodioxol-5-yl) -2- {5- [3- (1,8-naphthyridine-2) in anhydrous CH ₂ Cl ₂ (10 mL). -Ill) propyl] -2H-tetraazol-2-yl} ethanone (469 mg, 1.2 mmol) solution was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was applied to a flash silica gel column and purified using 5% MeOH / EtOAc to give a mixture of cis and trans isomers (480 mg). LC-MS (MH +) = 473.

  Step 5: Ethyl (2E) -3- (1,3-benzodioxol-5-yl) -4- {5- [3- (1,8-naphthyridin-2-yl) propyl] -1H-tetra Synthesis of Azol-1-yl} but-2-enoate

  1- (1,3-Benzodioxol-5-yl) -2- {5- [3- (1,8-naphthyridin-2-yl) propyl] -1H-tetraazol-1-yl as starting material } Using ethanone, ethyl (2E) -3- (1,3-benzodioxol-5-yl) -4- {5- [3- (1,8-naphthyridin-2-yl) propyl] -2H -The same synthesis method as in the case of -tetraazol-2-yl} but-2-enoate was carried out. LC-MS (MH +) = 473.

  Step 6: Ethyl 3- (1,3-benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Of Propyl] -2H-tetraazol-2-yl} butanoate

Ethyl (2E) -3- (1,3-benzodioxol-5-yl) -4- {5- [3- (1,8-naphthyridine-2-yl) in EtOH at room temperature under 5 psi Yl) propyl] -2H-tetraazol-2-yl} but-2-enoate (480 mg) was hydrogenated with 20% Pd (OH) ₂ / C. After 6 hours, the reaction was complete. Pd (OH) ₂ / C was filtered and the filtrate was concentrated to give the desired product (435 g). LC-MS (MH +) = 479.

  Step 7: Ethyl 3- (1,3-benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Synthesis of Propyl] -1H-tetraazol-1-yl} butanoate

  Ethyl (2E) -3- (1,3-benzodioxol-5-yl) -4- {5- [3-1,8-naphthyridin-2-yl) propyl] -1H-tetraazole as starting material -1-yl} but-2-enoate and ethyl 3- (1,3-benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro -1,8-naphthyridin-2-yl) propyl] -2H-tetraazol-2-yl} butanoate.

  Step 8: 3- (1,3-benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl ] -2H-Tetraazol-2-yl} butanoic acid synthesis

Ethyl 3- (1,3-benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) as starting material Propyl] -2H-tetraazol-2-yl} butanoate was performed in the same manner as in the previous examples. ¹ H NMR (500 MHz, DMSO-d6) δ 1.83 (m, 2H), 1.98 (m, 2H), 2.64 (m, 3H), 2.73 (m, 3H), 2.81 (t, 2H), 3.42 (m , 2H), 3.64 (m, 1H), 4.85 (m, 2H), 5.93 (d, 2H), 6.55 (m, 2H), 6.70 (d, 1H), 6.88 (d, 1H), 7.59 (d, ^{... 1H), 8.37 (} bs, 1H) C 23 H 26 N 6 O 4 1.1TFA 0.25 H2O analysis of calculated values: C 52.15 H 4.79 N 14.48 Found:. C 52.20 H 4.68 N 14.49 .

  3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1H -Tetraazol-1-yl} butanoic acid synthesis

3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl as starting material ] -1H-tetraazol-1-yl} butanoate was used in the same manner as in the previous examples. ¹ H NMR (400 MHz, DMSO-d6) δ 1.84 (m, 4H), 2.58-2.85 (m, 8H), 3.41 (m, 2H), 3.50 (m, 1H), 4.43-4.63 (m, 2H) , 5.92 (d, 2H), 6.50 (d, 1H), 6.55 (d, 1H), 6.72 (d, 1H), 6.79 (s, 1H), 7.61 (d, 1H), 8.15 (bs, 1H). ^{.. LC-MS (MH +} ) = 451. C 23 H 26 N 6 O 4 1.6TFA 0.25H2O analysis of calculated values: C 49.37 H 4.44 N 13.18 Found:. C 49.38 H 4.27 N 13.39 .
Reaction scheme 33

  3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] -1H -Pyrazol-5-yl} butanoic acid synthesis

  Step 1: Synthesis of ethyl 3- (1,3-benzodioxol-5-yl) -4- (5-oxo-2,5-dihydro-1H-pyrazol-3-yl) butanoate

3- (1,3-benzodioxol-5-yl) -7-ethoxy-5,7-dioxoheptanoic acid (1.0 g, 3.1 mmol) in EtOH (6 mL) at 45 ° C. ) Was added hydrazine monohydrate (165 μL, 3.4 mmol). The resulting solution was heated at 45 ° C. for 7 hours and allowed to cool to room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in absolute EtOH (7 mL) and 4N HCl in dioxane (7 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and partitioned between saturated aqueous NaHCO ₃ (20 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (15 mL, 2 times). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. A brown solid (880 mg, 2.8 mmol, 89%) was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 1.04 (t, 3H), 2.51-2.63 (m, 2H), 2.72 (m, 2H), 3.25 (m, 1H), 3.93 (m, 2H), 5.09 (s, 1H), 5.95 (s, 2H), 6.65 (dd, 1H), 6.77 (d, 1H), 6.85 (d, 1H). LC-MS (MH +) = 319.

  Step 2: Ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Synthesis of ethoxy] -1H-pyrazol-5-yl} butanoate

Ethyl 3- (1,3-benzodioxol-5-yl) -4- (5-oxo-2,5-dihydro-1H— in anhydrous THF (4 mL) at room temperature under Ar gas Pyrazol-3-yl) butanoate (300 mg, 0.94 mmol), 2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethanol (178 mg, 1.0 mmol) and triphenylphosphine To (296 mg, 1.1 mmol) was added DEAD (173 μL, 1.1 mmol). The reaction mixture was stirred overnight. The reaction mixture was quenched into H ₂ O (5 mL) and extracted with EtOAc (5 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 10% MeOH / EtOAc as eluent. An oil (117 mg, 0.24 mmol, 26%) was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 1.05 (t, 3H), 1.74 (m, 2H), 2.53-2.64 (m, 4H), 2.78 (m, 4H), 3.20-3.31 (m, 3H) , 3.93 (dq, 2H), 4.21 (t, 2H), 5.27 (s, 1H), 5.95 (s, 2H), 6.29 (m, 2H), 6.64 (dd, 1H), 6.77 (d, 1H), 6.84 (d, 1H), 7.03 (d, 1H), 11.5 (bs, 1H). LC-MS (MH +) = 479.

  Step 3: 3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy ] -1H-pyrazol-5-yl} butanoic acid synthesis

Ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) as starting material Ethoxy] -1H-pyrazol-5-yl} butanoate was used in the same synthesis method as in the previous examples. ¹ H NMR (400 MHz, DMSO-d6) δ 1.82 (m, 2H), 2.41-2.56 (m, 2H), 2.75 (m, 4H), 3.04 (t, 2H), 3.24 (m, 1H), 3.41 (m, 2H), 4.26 (t, 2H), 5.29 (s, 1H), 5.95 (s, 2H), 6.65 (m, 2H), 6.77 (d, 1H), 6.83 (d, 1H), 7.61 ( ^{.. d, 1H), 8.09} (bs, 1H) LC-MS (MH +) = 451. C 24 H 26 N 4 O 5 2.6TFA analysis of calculated values: C 46.95 H 3.86 N 7.50 Found:. C 46.74 H 3.74 N 7.78.

3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] isoxazol-5-yl} butanoic acid Synthesis of
Reaction scheme 34

  Step 1: Synthesis of ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [3- (N-BOC amino) propoxy] isoxazol-5-yl}} butanoate

To ethyl 3- (1,3-benzodioxol-5-yl) -4- (3-hydroxyisoxazol-5-yl) butanoate (890 mg, 2.8 mmol) in anhydrous THF (11 mL) Triphenylphosphine (892 mg, 3.4 mmol) and t-butyl N- (3-hydroxypropyl) -carbamate (581 μL, 3.4 mmol) were added. The temperature of the reaction mixture was lowered to 0 ° C. and DEAD (535 μL, 3.4 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography using 50% EtOAc / hexane as eluent. A yellow oil (890 mg, 1.9 mmol, 67%) was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 1.07 (t, 3H), 1.35 (s, 9H), 1.77 (m, 2H), 2.54-2.73 (m, 2H), 2.99 (m, 4H), 3.33 (m, 1H), 3.95 (dq, 2H), 4.07 (t, 2H), 5.81 (s, 1H), 5.97 (s, 2H), 6.68 (dd, 1H), 6.77 (d, 1H), 6.87 ( t, 1H), 6.92 (d, 1H).

  Step 2: Synthesis of ethyl 4- [3- (3-aminopropyl) isoxazol-5-yl] -3- (1,3-benzodioxol-5-yl) butanoate

CH ₂ Cl ₂ (7 mL) of ethyl 3- (1,3-benzodioxol-5-yl) in in -4- {3- [3- (N- BOC amino) propyl] isoxazol-5-yl} To butanoate (880 mg, 1.8 mmol) was added TFA (7 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and partitioned between saturated aqueous NaHCO ₃ (20 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 15 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. A yellow oil (677 mg, 1.8 mmol, 99%) was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 1.07 (t, 3H), 1.83 (m, 2H), 2.55-2.77 (m, 5H), 2.98 (m, 2H), 3.34 (m, 1H), 3.95 (dq, 2H), 4.14 (t, 2H), 5.83 (s, 1H), 5.97 (s, 2H), 6.68 (dd, 1H), 6.77 (d, 1H), 6.92 (d, 1H) .LC− MS (MH +) = 377.

  Step 3: Ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [3- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] isoxazole-5 Synthesis of il} butanoate

Ethyl 4- [3- (3-aminopropoxy) isoxazol-5-yl] -3- (1,3-benzodioxol-5-yl in anhydrous pyridine (8 mL) at 95 ° C. under Ar gas Yl) butanoate (670 mg, 1.8 mmol) was added 2-methylthio-2-imidazoline hydroiodic acid hydroxide (537 mg, 2.2 mmol). After 5 hours at 95 ° C., the solvent was removed under reduced pressure. The resulting residue was purified by flash column chromatography using 10% MeOH / CH ₂ Cl ₂ / NH ₄ OH as eluent. A yellow oil (621 mg, 1.4 mmol, 78%) was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 1.07 (t, 3H), 1.90 (m, 2H), 2.55-2.73 (m, 2H), 2.99 (m, 2H), 3.23 (m, 2H), 3.35 (m, 1H), 3.56 (s, 4H), 3.95 (dq, 2H), 4.12 (t, 2H), 5.82 (s, 1H), 5.97 (s, 2H), 6.68 (dd, 1H), 6.78 ( d, 1H), 6.93 (d, 1H), 8.21 (bs, 1H). LC-MS (MH +) = 445.

  Step 4: 3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] isoxazol-5-yl } Production of butanoic acid

Ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [3- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] isoxazole-5 as starting material Il} butanoate was used and the same synthesis method as in the above example was used. ¹ H NMR (400 MHz, DMSO-d6) δ 1.90 (m, 2H), 2.49-2.65 (m, 2H), 2.98 (m, 2H), 3.23 (q, 2H), 3.33 (m, 1H), 3.56 (s, 4H), 4.12 (t, 2H), 5.80 (s, 1H), 5.97 (s, 2H), 6.68 (dd, 1H), 6.78 (d, 1H), 6.91 (d, 1H), 8.31 ( ^{... t, 1H),} 12.14 (bs, 1H) LC-MS (MH +) = 417. C 20 H 24 N 4 O 6 1.3TFA 0.25H 2 O analysis results, calculated: C 47.69 H 4.57 N 9.84 Found: C 47.66 H 4.46 N 10.06.

3- [2- (4-Chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ) Ethoxy] isoxazol-5-yl} butanoic acid synthesis
Reaction scheme 35

  Step 1: Synthesis of 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -7-ethoxy-5,7, -dioxoheptanoic acid

The same synthesis method as in the above example was performed using 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] dihydro-2H-pyran-2,6-dione as a starting material. . The compound was purified by supercritical fluid chromatography using a cyano column. ¹ H NMR (400 MHz, DMSO-d6) δ 1.15 (t, 3H), 2.56-2.76 (m, 2H), 3.08 (d, 2H), 3.60 (s, 2H), 3.86 (m, 1H), 4.05 (q, 2H), 7.54 (d, 2H), 7.70 (s, 1H), 7.89 (d, 2H), 12.35 (bs, 1H). LC-MS (MH +) = 397.

  Step 2: Synthesis of ethyl 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- (3-hydroxyisoxazol-5-yl) butanoate

Synthesis method similar to the above example using 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -7-ethoxy-5,7, -dioxoheptanoic acid as starting material I went there. ¹ H NMR (400 MHz, DMSO-d6) δ 1.12 (t, 3H), 2.70-2.89 (m, 2H), 3.01-3.17 (m, 2H), 3.85 (m, 1H), 4.03 (q, 2H) , 5.77 (s, 1H), 7.55 (d, 2H), 7.71 (s, 1H), 7.88, (d, 2H), 11.05 (s, 1H). LC-MS (MH +) 393.

  Step 3: Ethyl 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl) ethoxy] isoxazol-5-yl} butanoate

Ethyl 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- (3-hydroxyisoxazole-5 in anhydrous THF (4.5 mL) under Ar gas -Yl) butanoate (195 mg, 0.50 mmol) was added to a solution of 2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethanol (98 mg, 0.55 mmol) and triphenylphosphine ( 157 mg, 0.60 mmol) was added. The temperature of the reaction mixture was lowered to 0 ° C. and diisopropyl azodicarboxylate (119 μL, 0.60 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was taken up in saturated aqueous NH ₄ Cl (15 mL), quenched and extracted with EtOAc (15 mL, 3 ×). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated to an oil. The oil was purified by flash column chromatography using EtOAc as the eluent. Ethyl 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) ethoxy] isoxazol-5-yl} butanoate was contaminated with triphenylphosphine oxide byproduct (226 mg, approximately 1: 1 ratio by NMR).

  Step 4: 3- [2- (4-Chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridine- Synthesis of 2-yl) ethoxy] isoxazol-5-yl} butanoic acid

Impure compound, ethyl 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [2- (5,6,7,8-tetrahydro-1,8- Naphthyridin-2-yl) ethoxy] isoxazol-5-yl} butanoate (220 mg) was dissolved in THF (1 mL). To this solution was added 1N NaOH (0.8 mL). The reaction mixture was stirred vigorously overnight. The reaction mixture was concentrated and the resulting residue was partitioned between H ₂ O (10 mL) and EtOAc (10 mL). The organic layer was removed and the aqueous layer was extracted with EtOAc (4 mL, once). The aqueous layer was concentrated to a small volume and acidified with 1N HCl. Acetonitrile was added to make a solution and the solution was purified by reverse phase HPLC using eluent (H ₂ O / HCl) / CH ₃ CN (0.5 mL concentrated HCl in 4 L H ₂ O). . Yellow solid, 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridine- 2-yl) ethoxy] isoxazol-5-yl} butanoic acid (105 mg) was obtained as the hydrochloride salt. ¹ H NMR (400 MHz, DMSO-d6) δ 1.80 (m, 2H), 2.63-2.84 (m, 4H), 3.03-3.21 (m, 4H), 3.41 (m, 2H), 3.84 (m, 1H) , 4.45 (t, 2H), 6.03 (s, 1H), 6.63 (d, 1H), 7.54 (m 3H), 7.71 (s, 1H), 7.88 (d, 2H), 8.12 (bs, 1H). LC ^{.. -MS (MH +) 526.} C 26 H 25 ClN 4 O 4 S 1.75HCl 5H 2 O analysis results, calculated: C 46.00 H 5.46 N 8.25 Found:. C 46.07 H 5.55 N 8.32 .

3-Benzo [1,3] dioxol-5-yl-4- {3- [2- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene-2- Yl) -ethoxy] -isoxazol-5-yl} -butyric acid; and 3-benzo [1,3] dioxol-5-yl-4- {3-oxo-2- [2- (6,7,8,9) -Tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl) -ethyl] -2,3-dihydro-isoxazol-5-yl} -butyric acid

Reaction scheme 35a

Step 1: Appropriate intermediate in 2- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl) -ethanol dioxane (5 mL) 0.86 g, 2.92 mmol) and 4N HCl solution were stirred at room temperature for 2 hours. The solvent was removed. The crude product was purified on a silica gel column eluting with dichloromethane / ethanol / ammonium hydroxide (95: 4.5: 0.5) to give 2- (6,7,8,9- 0.466 g of tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl) -ethanol was obtained. ¹ H-NMR (CD ₃ OD): δ 2.00 (2H, m, CH ₂ ), δ 2.78 (2H, t, CH ₂ ), δ 3.85 (2H, t, CH ₂ ) _, δ 4.10 (2H, t, CH ₂ ) _, δ 6.58 (1H, d, Py-H), δ 7.10 (1H, d, Py-H).

Step 2: 3-Benzo [1,3] dioxol-5-yl-4- {3- [2- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene 2-yl) -ethoxy] -isoxazol-5-yl} -butyric acid ethyl ester; and 3-benzo [1,3] dioxol-5-yl-4- {3-oxo-2- [2- (6, 7,8,9-Tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl) -ethyl] -2,3-dihydro-isoxazol-5-yl} -butyric acid ethyl ester

  To a solution of 3-benzo [1,3] dioxol-5-yl-4- (3-hydroxy-isoxazol-5-yl} -butyric acid ethyl ester (0.41 g, 1.29 mmol) and tetrahydrofuran (5 mL) was added tris. Phenylphosphine (0.44 g, 1.67 mmol) and diethyl azodicarboxylate (0.28 mL, 1.67 mmol) were added at 0 ° C. The solution was stirred for 30 minutes, a suitable intermediate (0 .26 g, 1.32 mmol) and tetrahydrofuran (5 mL) were added and the resulting solution was stirred overnight at room temperature The solvent was removed and the crude product was inverted with an acetonitrile / water (5%) gradient. Purification by phase HPLC yielded 0.380 mg of a mixture of the two products, which was used in the next step without further purification.

Step 3: 3-Benzo [1,3] dioxol-5-yl-4- {3- [2- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene) 2-yl) -ethoxy] -isoxazol-5-yl} -butyric acid; and 3-benzo [1,3] dioxol-5-yl-4- {3-oxo-2- [2- (6,7, 8,9-Tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl) -ethyl] -2,3-dihydro-isoxazol-5-yl} -butyric acid

A mixture of the above step (0.38 g) and a solution of 1N sodium hydroxide in ethanol (50 mL) was stirred overnight. The solvent was removed. The crude product was purified by reverse phase HPLC with an acetonitrile / water (5%) gradient to give two products (0.27 g and 0.053 g, respectively). First product: ¹ H-NMR (CD ₃ CD): δ 2.18 (2H, m, CH ₂ ), 2.60 (2H, m, CH ₂ ), 2.95 (2H, m, CH ₂ ), 3.08 (2H , t, CH ₂ ), 3.38 (1H, m, CH) _, 3.60 (2H, t, CH ₂ ) _, 4.28 (2H, t, CH ₂ ) _, 4.90 (2H, t, CH ₂ ), 5.59 (1H, s, CH), 5.90 (2H, s, CH ₂ ), 6.56 (1H, d, Py-H), 6.68 (1H, d, Ar-H), 6.75 (2H, m, Ar-H), 7.30 ( _{.. 1H, d, Py-} H) C 24 H 25 N 3 O 7 1.0 TFA, 1.0 H 2 O analysis results, calculated: C, 52.09; H, 4.71 ; N, 7.01, Found: C, 52.16 H, 4.35; N, 7.28. Second product: ¹ H-NMR (CD ₃ CD): δ 2.18 (2H, m, CH ₂ ), 2.60 (2H, m, CH ₂ ), 2.85 (2H, m, CH ₂ ), 2.95 (2H , t, CH ₂ ), 3.32 (1H, m, CH) _, 3.60 (2H, t, CH ₂ ) _, 4.08 (2H, t, CH ₂ ) _, 4.28 (2H, t, CH ₂ ), 5.30 (1H, s, CH), 5.93 (2H, s, CH ₂ ), 6.32 (1H, d, Py-H), 6.70 (1H, m, Ar-H), 6.78 (2H, m, Ar-H), 7.30 ( 1H, d, Py-H) .C ₂₄ H ₂₅ N ₃ O ₇ .2.0 TFA, 1.4 H ₂ O analysis, calculated: C, 46.66; H, 4.17; N, 5.83, measured: C, 46.32 H, 3.88; N, 6.25.

  3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6 -Ill) ethoxy] isoxazol-5-yl} butanoic acid, preparation of TFA

Reaction scheme 36

  Process 1

To a solution of the appropriate intermediate (568 mg, 1.78 mmol) and triphenylphosphine (447 mg, 1.78 mmol) in 10 mL of TFA under N ₂ at room temperature was added diethyl azodicarboxylate (6 mL) in diethyl azodicarboxylate ( 292 mg, 1.78 mmol) solution was added and stirred for 15 minutes. The product of Example 68 Step 6 (320 mg, 1.78 mmol) was added. The resulting reaction mixture was stirred at room temperature for 3 hours. The THF was evaporated and the residue was purified by HPLC with an acetonitrile gradient of 15-50% in 30 minutes to give 80 mg of product A and 150 mg of product B (both yellow oil).

  Process 2

Step 1 product B (150 mg, 0.31 mmol) was dissolved in 2 mL of methanol and 2 mL of 1N sodium hydroxide. The reaction was stirred at room temperature for 18 hours, acidified with 1 mL of trifluoroacetic acid and concentrated. The residue was purified by HPLC with an acetonitrile gradient of 15-50% in 30 minutes to give 110 mg of the desired product as a yellow oil. FAB-MS: (MH +) = 454. H NMR (400 MHz, CD ₃ OD) δ 2.61 (m, 2H), 3.00 (m, 2H), 3.12 (t, 2H), 3.40 (m, 1H), 3.64 (t, 2H), 4.28 (t, 2H), .4.41 (t, 2H), 5.60 (s, 1H), 5.89 (s, 2H), 6.68 (m, 4H), 7.31 (d, 1H). C _{23 H 23 N 3 O 7 1.5} CF 3 COOH analysis of calculated values: C, 50.01; H, 3.95 ; N, 6.73 Found:. 49.98; H, 4.29; N, 7.02.

  3- (1,3-Benzodioxol-5-yl) -4- {2- [2- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6 -Yl) ethyl] -3-oxo-2,3-dihydroisoxazol-5-yl} butanoic acid, preparation of TFA

The appropriate intermediate (80 mg, 0.17 mmol) was dissolved in 1.5 mL of methanol and 1.5 mL of 1N sodium hydroxide solution. The reaction was stirred at room temperature for 18 hours, acidified with 1 mL of trifluoroacetic acid and concentrated. The residue was purified by HPLC with an acetonitrile gradient of 15-50% in 30 minutes to give 37 mg of the desired product as a yellow oil. FAB-MS: (MH +) = 454.H NMR (500 MHz, CD ₃ OD) δ 2.65 (m, 2H), 2.98 (m, 4H), 3.41 (m, 1H), 3.64 (t, 2H), 4.17 (t, 2H), 4.28 (t, 2H), 5.41 (s, 1H), 5.90 (d, 2H), 6.28 (d, 1H), 6.74 (m, 2H), 6.80 (d, 1H), 7.18 ( d, 1H).
Reaction scheme 37

  3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (1,2,3,5-tetrahydropyrido [2,3-e] [1,4] oxazepine -8-yl) ethoxy] isoxazol-5-yl} butanoic acid, preparation of TFA

  Process 1

  To a solution of the appropriate intermediate shown in the previous example (408 mg, 1.28 mmol) and triphenylphosphine (336 mg, 1.28 mmol) in 10 mL of THF under nitrogen at room temperature in THF (6 mL). Diethyl azodicarboxylate (222 mg, 1.28 mmol) solution was added and stirred for 15 minutes. Appropriate intermediate (360 mg, 2.0 mmol) was added. The resulting reaction mixture was stirred at room temperature for 3 hours. The THF was evaporated and the residue was purified by HPLC with an acetonitrile gradient of 15-50% to give 70 mg of product A and 135 mg of product B (both yellow oil).

  Process 2

Step 1 product B (135 mg, 0.27 mmol) was dissolved in 2 mL of methanol and 2 mL of 1N sodium hydroxide solution. The reaction mixture was stirred at room temperature for 18 hours, acidified with 1 mL of trifluoroacetic acid and concentrated. The residue was purified by HPLC with an acetonitrile gradient of 15-50% in 30 minutes to give 97 mg of the desired product as a yellow oil. FAB-MS: (MH +) = 468. H NMR (400 MHz, CD ₃ OD) δ 2.61 (m, 2H), 3.00 (m, 2H), 3.20 (t, 2H), 3.40 (m, 1H), 3.67 (t, 2H), 3.98 (t, 2H), 4.46 (t, 2H), 4.74 (s, 2H), 5.60 (s, 1H), 5.89 (s, 2H), 6.69 (m, 3H), 6.86 ( d, 1H), 7.78 (d, 1H) .C ₂₄ H ₂₅ N ₃ O ₇ 1.5 CF ₃ COOH analysis result, measured value: C, 50.79; H, 4.18; N, 6.58. Actual value: 50.87; H, 4.38; N, 6.69.

  3- (1,3-Benzodioxol-5-yl) -4- {3-oxo-2- [2- [1,2,3,5-tetrahydropyrido [2,3-e] [1 , 4] Oxazepine-8-yl] ethyl] -2,3-dihydroisoxazol-5-yl} butanoic acid, preparation of TFA

Step 1 product A (70 mg, 0.14 mmol) was dissolved in 1.5 mL of methanol and 1.5 mL of 1N sodium hydroxide solution. The reaction was stirred at room temperature for 18 hours, acidified with 1 mL of trifluoroacetic acid and concentrated. The residue was purified by HPLC with an acetonitrile gradient of 15-50% in 30 minutes over 30 minutes to give the desired product mg as a yellow oil. FAB-MS: (MH +) = 468.H NMR (400 MHz, CD ₃ OD) δ 2.64 (m, 2H), 2.97 (m, 2H), 3.09 (t, 2H), 3.39 (m, 1H), 3.70 (t, 2H), 4.00 (t, 2H), 4.21 (t, 2H), 4.75 (s, 2H), 5.41 (s, 1H), 5.90 (dd, 2H), 6.54 (d, 1H), 6.75 ( m, 3H), 7.70 (d, 1H).

  3- (1,3-Benzodioxol-5-yl) -4- (3- {2- [5- (methoxymethyl) -6- (methylamino) pyridin-2-yl] ethoxy} isoxazole-5 -Il) Production of butanoic acid, TFA

Reaction scheme 38

  Process 1

  Same as described in previous examples.

  Process 2

To a solution of the product of step 1 (7 g, 44.58 mmol) in DMSO (35 mL) at room temperature is added KOH powder (7.5 g, 133.74 mmol) followed by MeI (4.2 mL, 66.66 mmol). 87 mmol) was added. After stirring at room temperature for 2 hours, the reaction was quenched with water. After extraction with Et ₂ O (3 times), the organic layer was washed, partitioned between water and EtOAc, washed with brine, dried over sodium sulfate, concentrated in vacuo and a yellow crystalline solid To give the title compound. 1 H NMR (400 MHz, CDCl ₃ ) δ 2.54 (s, 3H), 3.47 (s, 3H), 4.50 (s, 2H), 7.10 (d, 1H), 7.70 (d, 1H).

  Process 3

The product of Step 2 (7.38 g, 43.03 mmol) and mCPBA (14.85 g, 86.06 mmol) were dissolved in CHCl ₃ (50 mL) and stirred at 50 ° C. overnight. The solution was concentrated in vacuo and purified by flash chromatography (silica, 98: 2: 0.5 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give white crystals. H NMR (400 MHz, CDCl ₃ ) δ 2.57 (s, 3H), 3.48 (s, 3H), 4.50 (s, 2H),) 7.20 (d, 1H), 7.30 (d, 1H).

  Process 4

Mixture of the product of step 3 (5.8 g, 30.85 mmol), methylamine (2M solution in THF, 30 mL, 60 mmol) and NaHCO ₃ (13 g, 154 mmol) in t-amyl alcohol (70 mL). Was heated at 90 ° C. in a pressurized test tube for 48 hours. The reaction was cooled, diluted with CH ₂ Cl ₂ and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica, 98: 2: 0.5 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give pale yellow crystals. H NMR (400 MHz, CDCl ₃ ) δ 2.50 (s, 3H), 3.26 (d, 3H), 3.37 (s, 3H), 4.50 (s, 2H),) 6.50 (d, 1H), 7.02 (d, 1H).

  Process 5

A solution of the product of Step 4 (7.38 g, 40.55 mmol), ion powder (3.4 g, 60.82 mmol), triphenylphosphine (10.64 g, 40.55 mmol) and acetic acid (100 mL). Heat and reflux for 1 hour. The solution was cooled, filtered through a celite bed and washed with ethyl acetate. The filtrate was concentrated and purified on a silica gel column eluting with 50% EtOAc / hexanes to give a yellow oil. H NMR (400 MHz, CDCl ₃ ) δ 2.41 (s, 3H), 3.00 (s, 3H), 3.29 (s, 3H), 4.36 (s, 2H),) 6.36 (d, 1H), 7.02 (d, 1H).

  Step 6

  A solution of the product of step 5 (3 g, 18.07 mmol), di-tert-butyl dicarbonate (7.86 g, 36 mmol) and DMAP (250 mg) in THF (5 mL) was heated and refluxed overnight. . The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (eluent, 30:70 ethyl acetate / hexane) gave a yellow oil.

  Step 7

A stirred solution of the product of step 6 (0.5 g, 1.88 mmol) in dry TFA (30 mL) was cooled (−78 ° C.) under nitrogen and the solution was added to a lithium diisopropylamide solution (THF / ethylbenzene / 2.0M in heptane, 2.6 mL, 5.26 mmol) was added and the resulting solution was stirred at −78 ° C. for 20 minutes. To this mixture was added diethyl carbonate (0.843 mL, 6.95 mmol). After 1 hour, the reaction was quenched with saturated NH ₄ Cl solution and allowed to warm to room temperature. The mixture is extracted three times with ethyl acetate and all the organic extracts are combined, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product, which is purified on silica gel. And purified by chromatography (eluent, 25% ethyl acetate / hexane). The desired product is a yellow oil. MHz, CDCl ₃ ) δ 1.19 (t, 3H), 1.35 (s, 9H), 3.16 (s, 3H), 3.32 (s, 3H), 3.74 (s, 2H), 4.10 (q, 2H), 4.22 ( s, 2H),) 7.15 (d, 1H), 7.76 (d, 1H).

  Process 8

To a solution of the product of step 7 (660 mg, 1.95 mmol) in dry THF (10 mL) at room temperature was added LiBH ₄ solution (2.0 M in THF, 1.17 mL, 2.34 mmol). The resulting mixture was heated to reflux. After 16 hours, the mixture was cooled to 0 ° C. and carefully quenched with water. The mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil.

  Step 9

A mixture of the product of Step 7 and 4M HCl in dioxane (4 mL) was stirred at room temperature for 4 hours and then concentrated at low temperature. The residue was dissolved in 4 mL of methanol and 1 g of NaHCO ₃ was added thereto. The resulting mixture was stirred at room temperature for 1 hour, filtered and concentrated in vacuo to give a yellow oil. H NMR (400 MHz, CD ₃ OD) δ 2.94 (t, 2H), 3.03 (s, 3H), 3.30 (s, 3H), 3.84 (t, 2H), 4.35 (t, 2H), 6.67 (d, 1H), 7.70 (d, 1H).

  Step 10

  To a solution of the product from Example 111 step 6 (652 mg, 2.04 mmol) and triphenylphosphine (525 mg, 2.04 mmol) in 8 mL of THF under nitrogen at room temperature was added diethyl in THF (3 mL). Azodicarboxylate (329 mg, 2.04 mmol) solution was added and stirred for 15 minutes. The product of step 9 (400 mg, 2.04 mmol) was added. The resulting reaction mixture was stirred at room temperature for 3 hours. The THF was evaporated and the residue was purified by HPLC with an acetonitrile gradient of 15-50% in 30 minutes to give a yellow oil.

  Step 11: 3- (1,3-benzodioxol-5-yl) -4- (3- {2- [5- (methoxymethyl) -6- (methylamino) pyridin-2-yl] ethoxy} Isoxazol-5-yl) butanoic acid:

The product of step 9 (100 mg, 0.21 mmol) was dissolved in 2 mL of methanol and 2 mL of 1N sodium hydroxide solution. The reaction was stirred at room temperature for 18 hours, acidified with 1 mL of trifluoroacetic acid and concentrated. The residue was purified by HPLC with an acetonitrile gradient of 15-50% in 30 minutes to give 57 mg of the desired product as a yellow oil. FAB-MS: (MH +) = 466.H NMR (500 MHz, CD ₃ OD) δ 2.63 (m, 2H), 3.00 (m, 2H), 3.13 (s, 3H), 3.29 (m, 2H), 3.40 (m, 4H), 4.42 (s, 2H), 4.48 (t, 2H), 5.62 (s, 1H), 5.88 (s, 2H), 6.70 (m, 4H), 7.76 (d, 1H).

  3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (5,5-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

Reaction scheme 39

  Step 1: Production of N- (6-bromopyridin-2-yl) -β-alanine

Commercially available 2-bromo-5-aminopyridine (25.46 g) was mixed with 18.9 mL of ethyl acrylate and 4.41 mL of glacial acetic acid was added to the resulting solution. The solution was heated at 130 ° C. for 3 days under an argon atmosphere. The reaction was cooled and 58 mL of 6N aqueous sodium hydroxide was added and heated at 100 ° C. for 40 minutes. After cooling the reaction mixture, the pH was adjusted to 5 with concentrated hydrochloric acid. The precipitate was collected and washed with fresh water followed by hexane. The mother liquor was washed with ethyl acetate or methylene chloride to give 6.6 g of product. ¹ H NMR, 400 MHz, DMSO δ 12.23 (1H, br.s); 7.27 (1H, dd, J = 8, 7 Hz); 7.00 (1H, br. T, J = 6 Hz); 6.63 (1H, d, J = 7 Hz); 6.46 (1H, d, J = 8 Hz); 3.39 (2H, q, J = 6.5 Hz); 2.49 (2H, t, J = 7 Hz).

  Step 2: Preparation of 7-bromo-2,3-dihydro-1,8-naphthyridin-4 (1H) -one

  The product from the previous step (6.6 g) was suspended in 99 g of polyphosphoric acid and heated at 120 ° C. for 40 minutes. The reaction mixture was transferred to a glass beaker, cooled, and placed in ice in portions and stirred until the viscous oil was completely dissolved. The solution was always kept at 0 ° C. The pH of the resulting solution was adjusted to be between 8 and 9 with cold concentrated ammonium hydroxide. The resulting solid was filtered from the solution, washed with water and dissolved in methylene chloride. The solution was washed with brine, dried (magnesium sulfate) and the solvent removed under reduced pressure. The resulting solid was dried under high vacuum and washed with absolute ethanol to give the desired product (1.1 g) whose purity was acceptable for use in the next step.

Process 3
¹ H NMR, 300 MHz, CDCl ₃ δ 7.88 (1H, d, J = 8 Hz); 6.87 (1H, d, J = 8 Hz); 5.54 (1H, br.s); 3.67 (2H, td, J = 7, 2 Hz); 2.72 (2H, t, J = 7 Hz).

  Step 4: Preparation of 7-bromo-4,4-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine

To a solution of 26 mL of methylene chloride was added 15.08 mL of a 1M solution of titanium tetrachloride in methylene chloride and cooled to -30 ° C. A solution of dimethylzinc (2.0 M in toluene, 7.54 mL) was added dropwise and the solution was stirred for 10 minutes. Ketone (produced from Step 2) was added in one portion and the reaction mixture was warmed to 25 ° C. over 2 hours. This solution was poured into 50 mL of ice water and extracted with methylene chloride. The organic layer was dried (magnesium sulfate) and evaporated to dryness to give a yellow oil that began to solidify upon standing. The crude reaction mixture was purified by column chromatography to give 261 g of the desired product. ¹ H NMR, 300 MHz, CDCl ₃ δ 7.19 (1H, d, J = 8 Hz); 6.67 (1H, d, J = 8 Hz); 5.25 (1H, br.s); 3.43 (2H, m); 1.68 (2H, distorted t, J ~ 7 Hz); 1.25 (6H, s).

  Step 5: 1 Preparation of 4- (5,5-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanenitrile

A flask in an inert gas atmosphere was charged with 4.5 mL of a 0.5 M solution of 3-cyanopropylzinc bromide. To this solution was added 131.7 mg of tetrakistriphenylphosphine palladium, followed by bromonaphthyridine produced in Step 3. Added. The reaction was very slow and warmed to 50 ° C. In an attempt to speed up the reaction, additional catalyst was added in portions at regular intervals. The reaction was quenched with a saturated solution of sodium chloride and then extracted with methylene chloride. The solution to a flash chromatography _{(SiO 2, 10% MeOH /} CH 2 Cl 2) and then purified on reverse phase chromatography to give the product 47mg of interest. ¹ H NMR, 300 MHz, CD ₃ CN δ 9.57 (1H, br.s); 7.70 (1H, d, J = 8 Hz); 6.55 (1H, d, J = 8 Hz); 3.50 (2H, br. t, J = 7 Hz); 2.79 (2H, t, J = 7 Hz); 2.46 (2H, t, J = 7 Hz); 2.02 (2H, p, J = 7 Hz); 1.73 (2H, distorted t , J = 7 Hz); 1.29 (6H, s).

  Step 6: Preparation of (1Z) -4- (5,5-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) -N-hydroxybutaneimidamide

The product from the previous step (47 mg, 0.13 mmol) was dissolved in 1-2 mL of absolute ethanol and 17.96 mg of potassium carbonate was added to this solution. The solution was stirred at 25 ° C. After 1 hour, 7.9 mL of 50 wt% aqueous hydroxylamine was added at regular intervals while the reaction was monitored by LCMS until most of the starting material was converted to product. The reaction mixture was evaporated to dryness, sucked under high vacuum and used as such in the next step without further purification. ¹ H NMR, 300 MHz, CD ₃ OD δ 7.32 (1H, d, J = 8 Hz); 6.37 (1H, d, J = 8 Hz); 3.35 (2H, t, J = 7 Hz); 2.50 (2H , t, J = 7 Hz); 2.07 (2H, t, J = 7 Hz); 1.83 (2H, p, J = 7 Hz); 1.62 (2H, t, J = 7 Hz); 1.20 (6H, s ).

  Step 7: 3- (1,3-benzodioxol-5-yl) -4- {3- [3- (5,5-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid

The material obtained from the previous step was dissolved in 1 mL of dioxane and 30 mg of anhydride was added to this solution. The reaction was heated at 60 ° C. for 1 day, the temperature was raised to 100 ° C. and stirred overnight. The solvent was evaporated to dryness and purified by reverse phase chromatography (gradient, H ₂ O / acetonitrile 0.1% HCl) to give 3.56 mg (purity, 16-20%) of the desired compound as the hydrochloride salt. ¹ H (CD ₃ CN): d 8.44 (1H, br.s); 7.68 (1H, d, J = 8 Hz); 6.82 (1H, d, J = 1 Hz); 6.76 (1H, d, J = 8 Hz); 6.73 (1H, dd, J = 8, 1 Hz); 6.52 (1H, d, J = 8 Hz); 5.93 (2H, s); 5.47 (1H, s); 3.61 (1H, p, 3.53 (2H, br.t, J = 6 Hz); 3.23 (1H, dd, J = 15, 7 Hz); 3.15 (1H, dd, J = 15, 7 Hz); 2.82 ( 1H, dd, J = 16, 7 Hz); 2.72 (4H, t, J = 7 Hz); 2.70 (1H, dd, J = 16, 7 Hz); 2.14 (2H, p, J = 7 Hz); 1.74 (1H, distorted t, J = 6 Hz); 1.28 (6H, s).

  3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine- 6-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

Reaction scheme 40

  Step 1: Synthesis of 6-methyl-2-nitropyridin-3-yl-trifluoromethanesulfonate

To a solution of 3-hydroxy-6-methyl-2-nitropyridine (2 g, 12.97 mmol, 1 eq) in CH ₂ Cl ₂ (150 mL) under nitrogen at 0 ° C., triethylamine (2.68 mL, 19.27 mmol, 1.48 eq) was added followed by trifluoromethanesulfonic anhydride (2.62 mL, 15.57 mmol, 1.2 eq). The mixture was stirred at 0 ° C. for 2 hours and then quenched with water. The organic layer was separated, washed with water and dried over magnesium sulfate. After filtration and concentration under reduced pressure, the crude mixture was subjected to flash chromatography on silica gel (15% EA / hexane) to give the desired product (3.65 g, yield: 98%) as a yellow oil. 1 H NMR (400 MHz, CDCl ₃ ) δ 2.70 (s, 3H), 7.59 (d, 1H), 7.81 (d, 2H).

  Step 2: Synthesis of ethyl N-methyl-N- (6-methyl-2-nitropyridin-3-yl) glycinate

To a solution of 6-methyl-2-nitropyridin-3-yl trifluoromethanesulfonate (7 g, 24.47 mmol, 1 eq) in toluene (40 mL) at room temperature under nitrogen was added sarcosine hydrochloride (9.4 g). 61.2 mmol, 2.5 eq) followed by triethylamine (8.51 mL, 61.2 mmol, 2.5 eq). The mixture was refluxed overnight under nitrogen. The reaction was cooled to room temperature and quenched with water. The mixture was extracted 3 times with ethyl acetate and all the organic extracts were combined, washed with brine and dried over Na ₂ SO ₄ . After filtration and concentration under reduced pressure, the crude mixture was subjected to flash chromatography on silica gel (20% EA / hexane) to give the desired product (4.3 g, yield: 69%) as a brown oil. H NMR (400 MHz, CDCl ₃ ) δ 1.026 (t, 3H), 2.50 (s, 3H), 2.95 (s, 3H), 3.88 (s, 2H), 4.20 (q, 2H), 7.27 (d, 1H ), 7.49 (d, 2H).

  Step 3: Synthesis of 1,6-dimethyl-1,4-dihydropyrido [2,3-b] pyrazin-3 (2H) -one

6-Methyl-2-nitropyridin-3-yl trifluoromethanesulfonate (4.3 g, 17 mmol) was added in ethanol solution at room temperature using 5 psi H ₂ and 20% Pd (OH) ₂ / C catalyst. Hydrogenated for hours. At the end of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The product was crystallized from 50% EA / hexane as a yellow crystalline solid. The mother liquor was concentrated and purified by flash chromatography on silica gel (50% EA / hexane) (1.44 g, yield: 46%). H NMR (400 MHz, CDCl ₃ ) δ 2.26 (s, 3H), 2.70 (s, 3H), 3.18 (t, 2H), 3.58 (m, 2H), 6.34 (d, 1H), 6.57 (d, 2H ).

  Step 4: Synthesis of 1,6-dimethyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine

LiAlH ₄ (214 mg, 5.64 mmol) was slowly added to 10 mL of anhydrous THF in a round bottom flask equipped with a stir bar and condenser. After stirring for 10 minutes, a solution of 1,6-dimethyl-1,4-dihydropyrido [2,3-b] pyrazin-3 (2H) -one (500 mg, 2.82 mmol) in 5 mL of anhydrous THF was added dropwise. . When the addition was complete, the reaction mixture was refluxed for 16 hours. The reaction was cooled to room temperature and quenched with 1M sodium hydroxide solution until the mixture became milky yellow. The precipitate was filtered off and washed 3 times with CH ₂ Cl ₂ . The filtrate and washings were combined, washed with brine and dried over magnesium sulfate. Filtration and concentration under reduced pressure afforded the desired product as a pale yellow oil that solidified on standing (420 mg, yield: 91%). H NMR (400 MHz, CDCl ₃ ) δ2.27 (s, 3H), 2.80 (s, 3H), 3.17 (t, 2H), 3.58 (m, 2H), 6.36 (d, 1H), 6.56 (d, 2H).

  Step 5: Synthesis of tert-butyl 1,6-dimethyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) -carboxylate

1,6-dimethyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine (1.14 g, 7 mmol), di-tert-butyl dicarbonate (2.29 g, 30 mL of THF). 10.5 mmol), DMAP (100 mg) and triethylamine (1.46 mL, 10.5 mmol) were refluxed under nitrogen for 72 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with brine and dried over sodium sulfate. After filtration and concentration under reduced pressure, the crude mixture was purified by flash chromatography on silica gel (40% EA / hexane) to give the desired product (1.6 g, yield: 90%) as a yellow oil. . H NMR (400 MHz, CDCl ₃ ) δ 1.51 (s, 9H), 2.40 (s, 3H), 2.90 (s, 3H), 3.28 (t, 2H), 3.83 (m, 2H), 6.78 (d, 1H ), 6.83 (d, 2H).

  Step 6: Synthesis of tert-butyl 6- (2-ethoxy-2-oxoethyl) -1-methyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) -carboxylate

Tert-butyl 1,6-dimethyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) -carboxylate (950 mg, 3.61 mmol) and 20 mL dry THF under nitrogen atmosphere A stirred solution of diethyl carboxylate (1.62 mL, 13.36 mmol) was cooled (−78 ° C.) and a lithium diisopropylamide solution (2M in THF / ethylbenzene / heptane, 5 mL, 10 mmol) was added dropwise. After 1 hour, the reaction was quenched with saturated NH ₄ Cl solution and allowed to warm to room temperature. The mixture is extracted three times with ethyl acetate and all organic extracts are combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (eluent). And 30% ethyl acetate / hexane). The desired fractions were combined and concentrated under reduced pressure to give the desired product F (1.05 g, yield: 87%) as a yellow solid. H NMR (400 MHz, CDCl ₃ ) δ 1.25 (t, 3H), 1.50 (s, 9H), 2.78 (s, 3H), 3.38 (t, 2H), 3.68 (s, 2H), 3.84 (t, 2H ), 4.14 (q, 2H), 6.86 (d, 1H), 6.95 (d, 2H).

  Step 7: Synthesis of tert-butyl 6- (2-hydroxyethyl) -1-methyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) -carboxylate

Tert-butyl-6- (2-ethoxy-2-oxoethyl) -1-methyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H)-in dry THF (50 mL) at room temperature To a solution of carboxylate (26.5 g, 79.01 mmol) was added LiBH ₄ solution (2.0 M in THF, 59.26 mL) and the resulting mixture was heated to reflux. After 16 hours, the mixture was cooled to 0 ° C. and the reaction was carefully quenched with water. The mixture was extracted 3 times with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (eluent, 1: 1 hexane / ethyl acetate). To give the desired product (17.3 g). H NMR (400 MHz, CDCl ₃ ) δ 1.55 (s, 9H), 2.73 (t, 2H), 2.80 (s, 3H), 3.30 (t, 2H), 3.78 (t, 2H), 3.85 (t, 2H ), 6.76 (d, 1H), 6.85 (d, 2H), 7.28 (s, 1H).

  Step 8: Synthesis of tert-butyl 6- (2-iodoethyl) -1-methyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) -carboxylate

The product of step (5.6 g, 19.09 mmol), triphenylphosphine (6.51 g, 24.82 mmol) and imidazole (1.82 g, 26) in a mixture of CH ₃ CN and dry ether (1: 1). .72 mmol) to a stirred and cooled (0 ° C.) solution of iodine (6.78 g, 26.72 mmol) was added and stirred for 2 hours. 150 mL of ether was added to the resulting mixture, washed sequentially with saturated aqueous Na ₂ S ₂ O ₃ and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 20% EtOAc / hexanes) to give a yellow solid. H NMR (400 MHz, CDCl ₃ ) δ 1.55 (s, 9H), 2.93 (s, 3H), 3.18 (t, 2H), 3.30 (t, 2H), 3.458 (t, 2H), 3.85 (t, 2H ), 6.85 (q, 2H). LC-MS (M + H) 404.

  Step 9: Synthesis of tert-butyl 6- (3-cyano-4-ethoxy-4-oxobutyl) -1-methyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) -carboxylate

NaH (620 mg, 24.55 mmol) was suspended in DMF (203 mL) under nitrogen at 0 ° C. Ethyl cyanoacetate (2.6 mL, 24.55 mmol) was added and the resulting mixture was stirred for 30 minutes at 0 ° C. To this reaction mixture was charged the product of step 8 (6.6 g, 16.37 mmol) in DMF (10 mL) and stirred at room temperature for 2 hours. The mixture was cooled to 0 ° C., quenched with water and extracted with EtOAc (3 ×). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 90% EtOAc / hexanes) to give a colorless oil (5.78 g). H NMR (400 MHz, CDCl ₃ ) δ 1.35 (q, 3H), 1.55 (s, 9H), 2.38 (m, 2H), 2.89 (t, 2H), 2.93 (s, 3H), 3.32 (t, 2H ), 3.85 (t, 2H), 3.90 (m, 1H), 4.30 (q, 2H), 6.85 (d, 2H). LC-MS (M + H) 389.

  Step 10: Synthesis of 4- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl) butanenitrile

Heat a mixture of the product of Step 9 (5.78 g, 14.88 mmol) and KOH (powder, 1.25 g, 22.32 mmol) in ethylene glycol (30 mL) under nitrogen at 150 ° C. for 3 hours. did. The mixture was cooled to 0 ° C. and partitioned between water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash chromatography (silica, 100% EtOAc) gave a colorless oil. H NMR (400 MHz, CDCl ₃ ) δ 2.00 (t, 2H), 2.32 (t, 2H), 2.63 (t, 23H), 2.82 (s, 3H), 3.20 (t, 2H), 3.56 (t, 2H ), 6.40 (d, 1H), 6.58 (d, 1H).

  Step 11: Synthesis of (1E) -N'-hydroxy-4- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl) butaneimidamide

A mixture of the product of Step 10 (500 mg, 2.31 mmol) and hydroxylamine (0.56 mL of a 50 wt% aqueous solution, 8.50 mmol) in ethanol (20 mL) under nitrogen was added at 60 ° C. Heated overnight. The mixture was cooled to room temperature and concentrated in vacuo to give a white solid. H NMR (400 MHz, CD ₃ OD) δ 1.80 (m, 2H), 2.05 (t, 2H), 2.45 (t, 2H), 2.75 (s, 3H), 3.15 (t, 2H), 3.55 (t, 2H), 6.35 (d, 1H), 6.60 (d, 1H).

  Step 12: 3- (1,3-benzodioxol-5-yl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b ] Pyrazin-6-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

A mixture of the product of Step 11 (260 mg, 1.04 mmol) and the product of Example 1 Step 3 (290 mg, 1.25 mmol) in 1,4-dioxane (20 mL) was heated at 90 ° C. overnight. . The reaction mixture was allowed to cool to room temperature and concentrated. The residue was purified by HPLC with an acetonitrile gradient of 5-50% in 30 minutes to give 200 mg of the desired product. H NMR (400 MHz, DMSO-d6) δ 1.95 (m, 2H), 2.58-2.80 (m, 6H), 3.85 (s, 3H), 3.10-3.35 (m, 5H), 3.60 (t, 2H), 5.86 (s, 2H), 6.54 (d, 1H), 6.63 (d, 1H), 6.75 (d, 1H), 7.90 (m, 2H). FAB-MS: (MH +) = 466, C ₂₄ H ₂₇ N _{.. 5 O 5 1.5 TFA 1.0} H 2 O analysis results, calculated: C, 49.54; H, 4.70 ; N, 10.70, Found: C, 49.29; H, 4.58 ; N, 11.06.

  3- (2-Methyl-1,3-benzothiazol-5-yl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] Pyrazin-6-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

Starting from 4- (2-methyl-2,3-dihydro-1,3-benzothiazol-5-yl) dihydro-2H-pyran-2,6 (3H) -dione using the method described in Example 118 Thus, the above compound was produced. ¹ H NMR (400 MHz, DMSO-d6) δ 1.95 (m, 2H), 2.58-2.80 (m, 6H), 3.85 (s, 3H), 3.10-3.35 (m, 5H), 3.60 (t, 2H) , 5.86 (s, 2H), 6.54 (d, 1H), 6.63 (d, 1H), 6.75 (d, 1H), 7.90 (m, 2H). FAB-MS: (MH +) = 493, C ₂₅ H _{28 .. N 6 O 3 S 1.8} TFA 0.5 H 2 O analysis results, calculated: C, 48.60; H, 4.39 ; N, 12.15, Found: C, 48.84; H, 4.71 ; N, 12.15.

  3- (3-Fluoro-4-methoxyphenyl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

The above compound was prepared using the method described in Example 118, starting from 4- (3-fluoro-4-methoxyphenyl) dihydro-2H-pyran-2,6 (3H) -dione. ¹ H NMR (400 MHz, DMSO-d6) δ 1.95 (m, 2H), 2.40-2.80 (m, 6H), 3.85 (s, 3H), 3.10-3.35 (m, 4H), 3.58 (m, 1H) , 3.60 (t, 2H), 3.80 (s, 3H), 6.40 (d, 1H), 6.75 (d, 1H), 6.95 (s, 1H), 6.95-7.05 (dd, 2H). FAB-MS :( MH +) = 493, C ₂₄ H ₂₈ FN ₅ O ₄ .1.3 TFA. 0.9 H ₂ O analysis, calculated: C, 51.12; H, 4.85; N, 11.21, found: C, 51.16; H, 4.98 N, 11.28.

  3- (6-Methoxypyridin-3-yl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid:

The above compound was prepared using the method described in Example 118, starting from 4- (6-methoxypyridin-3-yl) dihydro-2H-pyran-2,6 (3H) -dione. ¹ H NMR (400 MHz, DMSO-d6) δ 1.95 (m, 2H), 2.60 (t, 2H), 2.70 (d, 2H), 2.80 (m, 2H), 2.85 (s, 3H), 3.20-3.40 (m, 4H), 3.65 (t, 2H), 3.680 (m, 1H), 3.82 (s, 3H), 6.560 (d, 1H), 6.78 (d, 1H), 6.90 (d, 1H), 7.70 ( _{.. q, 1H), 7.96} (d, 1H) FAB-MS: (MH +) = 453, C 23 H 28 N 6 O 4 3.1 TFA analysis of calculated values: C, 43.51; H, 3.89 ; N, 10.43, found: C, 43.36; H, 4.198; N, 10.19.

3- (1,3-Benzodioxol-5-yl) -4- (3-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl] thio } -1H-1,2,4-triazol-5-yl) butanoic acid synthesis
Reaction scheme 41

Step 1: Synthesis of 5- [2- (aminocarbonothionyl) hydrazino] -3- (1,3-benzodioxol-5-yl) -5-oxopentanoic acid

  To 4- (1,3-benzodioxol-5-yl) dihydro-2H-pyran-2,6 (3H) -dione (1.0 g, 4.3 mmol) in benzene (17 mL) Semicarbazide (428 mg, 4.7 mmol) was added. The reaction was refluxed (7 mL of THF added to increase solubility). After 3 hours at reflux, the reaction mixture was concentrated to give the desired product (1.4 g) as a white solid. The compound contained a small amount of impurities and was used as such in the next step. LC-MS (MH +) = 326.

Step 2: Synthesis of 3- (1,3-benzodioxol-5-yl) -4 (5-thioxo-2,5-dihydro-1H-1,2,4-triazol-3-yl) butanoic acid

  5- [2- (aminocarbonothionyl) hydrazino] -3- (1,3-benzodioxol-5-yl) -5-oxopentanoic acid (1.4 g, 4.3 mmol) was added to 5% NaOH. Aqueous solution (20 mL) was added. The reaction mixture was heated at 100 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature and acidified to pH about 4. The mixture was extracted with EtOAc (40 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated to give the desired product (156 mg) as a brown solid. LC-MS (MH +) = 308.

Step 3: 3- (1,3-Benzodioxol-5-yl) -4- (3-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethyl] thio} -1H-1,2,4-triazol-5-yl) butanoic acid

3- (1,3-benzodioxol-5-yl) -4- (5-thioxo-2,5-dihydro-1H-1 in anhydrous DMF (9 mL) at 60 ° C. under Ar gas , 2,4-Triazol-3-yl) butanoic acid (155 mg, 0.50 mmol) and K ₂ CO ₃ (145 mg, 1.1 mmol) were added to 7- (2-bromoethyl in anhydrous DMF (3 mL). ) -1,2,3,4-Tetrahydro-1,8-naphthyridine (133 mg, 0.55 mmol) solution was added. After stirring at 60 ° C. for 4 hours, the reaction mixture was concentrated. The residue was acidified with 1N HCl and purified by reverse phase HPLC using (H ₂ O / HCl) / CH ₃ CN (0.5 mL concentrated HCl in 4 L H ₂ O) as eluent. The HCl salt of the desired compound (47 mg) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.81 (m, 2 H), 2.50-2.71 (m, 2 H), 2.73 (t, 2 H), 2.96 (m, 2 H), 3.02 (t , 2 H), 3.43 (m, 5 H), 5.93 (s, 2 H), 6.52 (d, 1 H), 6.64 (dd, 1 H), 6.75 (d, 1 H), 6.85 (d, 1 H), 7.58 (d, 1 H), 8.01 (bs, 1 H); mass spectrometry of C ₂₃ H ₂₅ N ₅ O ₄ S (ESI +) m / z 468.1721 (M + H) ⁺ .C ₂₃ H ₂₅ N Analytical result of ₅ O ₄ S 2HCl ^. 1.3H ₂ O: Calculated value: C 48.99 H 5.29 N 12.42 ^. Found: C 48.69 H 5.31 N 12.34.

  3- (1,3-Benzodioxol-5-yl) -4- (1-methyl-5-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ) Ethyl] thio} -1H-1,2,4-triazol-3-yl) butanoic acid synthesis

Step 1: Synthesis of 5- [2- (aminocarbonothioyl) -2-methylhydrazino] -3- (1,3-benzodioxol-5-yl) -5-oxopentanoic acid

  To 4- (1,3-benzodioxol-5-yl) dihydro-2H-pyran-2,6 (3H) -dione (1.0 g, 4.3 mmol) in anhydrous THF (20 mL). 2-Methyl-3-thiosemicarbazide (494 mg, 4.7 mmol) was added. The reaction mixture was refluxed for 3 hours. The reaction mixture was concentrated to give the desired product (1.5 g). LC-MS (MH +) = 340.

Step 2: 3- (1,3-benzodioxol-5-yl) -4 (1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) Synthesis of butanoic acid

5- [2- (aminocarbonothionyl) -2-methylhydrazino] -3- (1,3-benzodioxol-5-yl) -5-oxopentanoic acid (1.5 g) was added to NaHCO _3. A 1M solution of (43 mL, 43 mmol) was added. The reaction mixture was heated at 80 ° C. overnight. The reaction mixture was cooled to room temperature and acidified to pH about 3. The resulting mixture was extracted with EtOAc (40 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated to give the desired product (950 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.50-2.64 (m, 2 H), 2.75-2.92 (m, 2 H), 3.43 (m, 1 H), 3.51 (s, 3 H), 5.96 (s, 2 H), 6.67 (dd, 1 H), 6.79 (d, 1 H), 6.88 (d, 1 H), 12.08 (bs, 1 H). LC-MS (MH +) = 322.

Step 3: 3- (1,3-Benzodioxol-5-yl) -4- (1-methyl-5-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridine- Synthesis of 2-yl) ethyl] thio} -1H-1,2,4-triazol-3-yl) butanoic acid

In a manner similar to Step 3 of Example 122, 3- (1,3-benzodioxol-5-yl) -4- (1-methyl-5-thioxo-4,5-dihydro-1H-1, 2,4-Triazol-3-yl) butanoic acid was used as starting material. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.81 (m, 2 H), 2.46-2.68 (m, 2 H), 2.73 (t, 2 H), 2.75-2.90 (m, 2 H), 3.03 (t, 2 H), 3.41 (m, 3 H), 3.49 (t, 2 H), 3.59 (s, 3 H), 5.92 (s, 2 H), 6.54 (d, 1 H), 6.67 (dd , 1 H), 6.75 (d, 1 H), 6.87 (d, 1 H), 7.58 (d, 1 H), 7.97 (bs, 1 H). LC-MS (MH +) = 482. C ₂₄ H _{27 ^{.. N 5 O 4 S HCl}} 1.75H 2 O analysis results, calculated: C 52.45 H 5.78 N 12.74 Found:. C 52.46 H 5.73 N 12.71 .

  3- (1,3-Benzodioxol-5-yl) -4- (4-methyl-5-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ) Ethyl] thio} -4H-1,2,4-triazol-3-yl) butanoic acid synthesis

Step 1: Synthesis of 3- (1,3-benzodioxol-5-yl) -5- {2-[(methylamino) carbonothioyl] hydrazino} -5-oxopentanoic acid

  In the same manner as in Step 1 of Example 123, 4-methyl-3-thiosemicarbazide was used as a starting material. LC-MS (MH +) = 340.

Step 2: 3- (1,3-Benzodioxol-5-yl) -4- (4-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl ) Synthesis of butanoic acid

In the same manner as in Step 2 of Example 123, the starting material was 3- (1,3-benzodioxol-5-yl) -5- {2- (methylamino) carbonothioyl} hydrazino} -5- Oxopentanoic acid was used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.51-2.77 (m, 2 H), 2.89-3.07 (m, 2 H), 3.31 (s, 3 H), 3.39 (m, 1 H), 5.97 (s, 2 H), 6.67 (dd, 1 H), 6.78 (d, 1 H), 6.92 (d, 1 H), 12.12 (bs, 1 H). LC-MS (MH +) = 322.

Step 3: 3- (1,3-Benzodioxol-5-yl) -4- (4-methyl-5-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridine- Synthesis of 2-yl) ethyl] thio} -4H-1,2,4-triazol-3-yl) butanoic acid

In a manner similar to Example 3, Step 3, using 3- (1,3-benzodioxol-5-yl) -4- (4-methyl-5-thioxo-4,5-dihydro-1H as a starting material. -1,2,4-Triazol-3-yl) butanoic acid was used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.81 (m, 2 H), 2.60-2.89 (m, 4 H), 3.08 (t, 2 H), 3.20-3.41 (m, 2 H), 3.43 (m, 2 H), 3.54 (m, 1 H), 3.58 (s, 3 H), 3.62 (t, 2 H), 5.97 (d, 2 H), 6.67 (d, 1 H), 6.78 (m , 2 H), 7.01 (s, 1 H), 7.61 (d, 1 H), 8.15 (bs, 1 H). Mass spectrum of C ₂₄ H ₂₇ N ₅ O ₄ S (ESI +) m / z482.1885 ( ^{... M + H) +} C 24 H 27 N 5 O 4 S 3HCl H 2 O analysis results, calculated: C 47.34 H 5.30 N 11.50 Found:. C 47.33 H 5.58 N 11.49 .

  3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine- 6-yl) ethoxy] isoxazol-5-yl} butanoic acid:

Reaction scheme 42

Step 1: Synthesis of 6-methyl-2-nitropyridin-3-yl) trifluoromethanesulfonate

To a solution of 3-hydroxy-6-methyl-2-nitropyridine (2 g, 12.97 mmol, 1 eq) in CH ₂ Cl ₂ (150 mL) under nitrogen at 0 ° C., triethylamine (2.68 mL, 19.27 mmol, 1.48 eq) was added, followed by trifluoromethanesulfonic anhydride (2.62 mL, 15.57 mmol, 1.2 eq). The mixture was stirred at 0 ° C. for 2 hours and then quenched with water. The organic layer was separated, washed with water and dried over magnesium sulfate. After filtration and concentration under reduced pressure, the crude mixture was purified by chromatography on silica gel (15% EA / hexane) to give the desired product (3.65 g, 98% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl ₃ ) δ 2.70 (s, 3H), 7.59 (d, 1H), 7.81 (d, 2H).

Step 2: Synthesis of ethyl N-methyl-N- (6-methyl-2-nitropyridin-3-yl) glycinate

To a solution of 6-methyl-2-nitropyridin-3-yl) trifluoromethanesulfonate (7 g, 24.47 mmol, 1 eq) in toluene (40 mL) under nitrogen at room temperature, sarcosine hydrochloride (9. 4 g, 61.2 mmol, 2.5 eq) followed by triethylamine (8.51 mL, 61.2 mmol, 2.5 eq). The mixture was refluxed overnight under nitrogen. The reaction mixture was cooled to room temperature and quenched with water. The mixture was extracted 3 times with ethyl acetate and all the organic extracts were combined, washed with brine and dried over sodium sulfate. After filtration and concentration under reduced pressure, the crude mixture was purified by chromatography on silica gel (20% EA / hexane) to give the desired product (4.3 g, 69% yield) as a brown oil. H NMR (400 MHz, CDCl ₃ ) δ 1.026 (t, 3H), 2.50 (s, 3H), 2.95 (s, 3H), 3.88 (s, 2H), 4.20 (q, 2H), 7.27 (d, 1H ), 7.49 (d, 2H).

Step 3: Synthesis of 1,6-dimethyl-1,4-dihydropyrido [2,3-b] pyrazin-3 (2H) -one

6-Methyl-2-nitropyridin-3-yltrifluoromethanesulfonate (4.3 g, 17 mmol) was hydrogenated in ethanol using 5 psi H ₂ and 20% Pd (OH) ₂ / C catalyst at room temperature for 2 hours. Added. Upon completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The product was crystallized from a 50% ethanol / hexane solution as a yellow crystalline solid. The mother liquor was concentrated and purified by flash chromatography on silica gel (50% ethanol / hexane) (1.44 g, 46% yield). H NMR (400 MHz, CDCl ₃ ) δ 2.26 (s, 3H), 2.70 (s, 3H), 3.18 (t, 2H), 3.58 (m, 2H), 6.34 (d, 1H), 6.57 (d, 2H ).

Step 4: Synthesis of 1,6-dimethyl-1,2,3,4-tetrahydropyridide [2,3-b] pyrazine

LiAlH ₄ (214 mg, 5.64 mmol) was slowly added to 10 mL of anhydrous THF in a round bottom flask equipped with a stir bar and condenser. After stirring for 10 minutes, a solution of 1,6-dimethyl-1,4-dihydropyrido [2,3-b] pyrazin-3 (2H) -one (500 mg, 2.82 mmol) in 5 mL of anhydrous THF was added dropwise. . When the addition was complete, the reaction mixture was refluxed for 16 hours. The reaction was cooled to room temperature and the reaction was quenched with 1M sodium hydroxide solution until the mixture became milky yellow. The precipitate was filtered off and washed 3 times with CH ₂ Cl ₂ . The filtrate and washings were combined, washed with brine and dried over magnesium sulfate. Filtration and concentration under reduced pressure afforded the desired product as a pale yellow oil that solidified on standing (420 mg, 91% yield). H NMR (400 MHz, CDCl ₃ ) δ 2.27 (s, 3H), 2.80 (s, 3H), 3.17 (t, 2H), 3.58 (m, 2H), 6.36 (d, 1H), 6.56 (d, 2H).

Step 5: Synthesis of tert-butyl 1,6-dimethyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) -carboxylate

1,6-dimethyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine (1.14 g, 7 mmol), di-tert-butyl dicarbonate (2.29 g, 30 mL of THF). 10.5 mmol), DMAP (100 mg) and triethylamine (1.46 mL, 10.5 mmol) were refluxed under nitrogen for 72 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with brine and dried over sodium sulfate. After filtration and concentration under reduced pressure, the crude mixture was purified by flash chromatography on silica gel (40% EA / hexane) to give the desired product (1.6 g, 90% yield) as a yellow oil. H NMR (400 MHz, CDCl ₃ ) δ 1.51 (s, 9H), 2.40 (s, 3H), 2.90 (s, 3H), 3.28 (t, 2H), 3.83 (m, 2H), 6.78 (d, 1H ), 6.83 (d, 2H).

Step 6: Synthesis of tert-butyl 6- (2-ethoxy-2-oxoethyl) -1-methyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) -carboxylate

Tert-butyl 1,6-dimethyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) -carboxylate (950 mg, 3.61 mmol) and 20 mL dry THF under nitrogen atmosphere To a cooled (−78 ° C.) stirred solution of diethyl carboxylate (1.62 mL, 13.36 mmol) was added dropwise a lithium diisopropylamide solution (2.0 M in THF / ethylbenzene / heptane, 5 mL, 10 mmol). After 1 hour, the reaction was quenched with saturated NH ₄ Cl solution and allowed to warm to room temperature. The mixture is extracted three times with ethyl acetate and all organic extracts are combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (eluent). And 30% ethyl acetate / hexane). The desired fractions were combined and concentrated under reduced pressure to give the desired product F (1.05 g, 87% yield) as a yellow solid. H NMR (400 MHz, CDCl ₃ ) δ 1.25 (t, 3H), 1.50 (s, 9H), 2.78 (s, 3H), 3.38 (t, 2H), 3.68 (s, 2H), 3.84 (t, 2H ), 4.14 (q, 2H), 6.86 (d, 1H), 6.95 (d, 2H).

Step 7: Synthesis of 2- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl) ethanol

Tert-butyl 6- (2-ethoxy-2-oxoethyl) -1-methyl-2,3-dihydropyrido [2,3-b] pyrazine-4 (1H) in dry THF (15 mL) at room temperature To a solution of carboxylate (1.05 g, 3.13 mmol) was added LiBH ₄ solution (2.0 M in THF, 1.88 mL) and the resulting mixture was heated to reflux. After 16 hours, the mixture was cooled to 0 ° C. and the reaction was carefully quenched with water (20 mL). After 10 minutes, the mixture was extracted three times with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue at this time was dissolved in CH ₂ Cl ₂ (3 mL), and 4 M HCl in dioxane (6 mL) was added in one portion at room temperature to this solution. After 4 hours, the mixture was concentrated under reduced pressure to give the crude product, which was chromatographed on silica gel (eluent, 98: 2: 0.5 dichloromethane / methanol / ammonium hydroxide) to give a gray solid. To give the desired product (390 mg). H NMR (400 MHz, CDCl ₃ ) δ 2.73 (t, 2H), 2.72 (s, 3H), 3.20 (t, 2H), 3.58 (m, 2H), 3.89 (t, 2H), 6.36 (d, 1H ), 6.58 (d, 2H).

Step 8: Synthesis of 3- (1,3-benzodioxol-5-yl) -7-ethoxy-5,7-dioxopentanoic acid

To a solution of anhydrous EtOAc (4.38 mL, 44.8 mmol) in anhydrous THF (25 mL) at −78 ° C. under Ar gas was added lithium diisopropylamide (2M in heptane / THF / ethylbenzene, 22.4 mL, 44.8 mmol) was added slowly. The resulting solution was stirred at −78 ° C. for 25 minutes and 4- (1,3-benzodiol-5-yl) dihydro-in anhydrous THF (170 mL) under −78 ° C. Ar gas. A solution of 2H-pyran-2,6 (3H) -dione (synthesis described in Step 3 of Example 1: 5.0 g, 21.3 mmol) was added dropwise via cannula. The reaction mixture was stirred at -78 ° C for 1.5 hours. The reaction was quenched with 2N HCl in ether (80 mL) and allowed to warm to room temperature. To the reaction mixture was added water (100 mL) and extracted with EtOAc (100 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 40% EtOAc / hexanes to give a white solid (5.61 g, 17.4 mmol, 82%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.25 (t, 3H), 2.55-2.73 (m, 2H), 2.90 (m, 2H), 3.34 (s, 2H), 3.60 (m, 1H), 4.15 ( q, 2H), 5.93 (s, 2H), 6.70 (m, 3H). LC-MS (M + Na) = 345.

Step 9: Synthesis of ethyl 3- (1,3-benzodioxol-5-yl) -4- (3-hydroxyisoxazol-5-yl) butanoate

  Hydroxylamine hydrochloride (1.1 g, 16.4 mmol) was dissolved in about 4.3 mL of 2N NaOH until a solution of pH 10.0 ± 0.3 (using a pH meter) was obtained. The solution was cooled to 0 ° C., and with vigorous stirring, 3- (1,3-benzodioxol-5-yl) -7-ethoxy-5,7 in 2N NaOH (ca. 8.5 mL). -A solution of dioxoheptanoic acid (4.8 g, 14.9 mmol) was added slowly while maintaining the pH of the reaction mixture at 10.0 ± 0.3 by dropwise addition of 2N NaOH. After complete addition, the reaction mixture was stirred at 0 ° C. for 1.5 hours and quenched into concentrated ice-cooled HCl (20 mL). The reaction mixture was warmed to room temperature and stirred for 4 hours. The resulting mixture was poured into ice water (200 mL) and extracted with EtOAc (200 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue (3.8 g) was dissolved in EtOH (15 mL) and 4N HCl in dioxane (15 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography using 50% EtOAc / hexane as eluent. A yellow oil (1.22 g, 3.8 mmol, 26%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 1.08 (t, 3H), 2.54-2.72 (m, 2H), 2.93 (m, 2H), 3.33 (m, 1H), 3.95 (q, 2H), 5.58 ( s, 1H), 5.97 (s, 2H). 6.68 (dd, 1H), 6.78 (d, 1H), 6.91 (d, 1H), 10.95 (s, 1H). LC-MS (MH +) = 320.

Step 10: Ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [2- (1-methyl-1,2,3,4-tetrahydropyrido [2,3- b] Synthesis of pyrazin-6-yl) ethoxy] isoxazol-5-yl} butanoate

2- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl) ethanol (110 mg, in anhydrous THF under nitrogen gas at 0 ° C. 0.57 mmol), ethyl 3- (1,3-benzodioxol-5-yl) -4- (3-hydroxyisoxazol-5-yl) butanoate (182 mg, 0.57 mmol) and triphenylphosphine ( To 164 mg, 0.63 mmol) was added diisopropyl azodicarboxylate (124 μL, 0.63 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residual oil was purified by reverse phase HPLC using (H ₂ O / TFA) / CH ₃ CN (2.5 mL TFA in 4 L water) as eluent to give 100 mg of the title compound as a yellow oil. H NMR (400 MHz, CD ₃ OD) δ 1.15 (t, 3H), 2.59-2.76 (m, 2H), 2.95-3.09 (m, 7H), 3.30 (t, 2H), 3.43 (m, 1H), 3.66 (t, 2H), 4.41 (q, 2H), 4.39 (t, 2H), 5.64 (s, 1H), 5.91 (s, 2H), 6.64-6.77 (m, 4H), 6.91 (d, 1H) .

Step 11: 3- (1,3-benzodioxol-5-yl) -4- {3- [2- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b Synthesis of pyrazin-6-yl) ethoxy] isoxazol-5-yl} butanoic acid

The product, ethyl 3- (1,3-benzodioxol-5-yl) -4- {3- [2- (1-methyl-1,2,3,4-tetrahydropyrido [2,3- b] pyrazin-6-yl) ethoxy] isoxazol-5-yl} butanoate (100 mg, 0.20 mmol) was dissolved in 2 mL of methanol and 2 mL of 1N sodium hydroxide solution. The reaction was stirred at room temperature overnight, concentrated, acidified with 1 mL trifluoroacetic acid, and reverse using (H ₂ O / TFA) / CH ₃ CN (2.5 mL TFA in 4 L water) as eluent. Purification by phase HPLC afforded 50 mg of the desired product as a dark green oil. FAB-MS: (MH +) = 467.H NMR (500 MHz, CD ₃ OD) δ 2.55-2.68 (m, 2H), 2.91-3.07 (m, 7H), 3.29 (t, 2H), 3.40 (m, 1H), 3.65 (t, 2H), 4.37 (t, 2H), 5.60 (s, 1H), 5.88 (s, 2H), 6.61-6.74 (m, 4H), 6.87 (d, 1H). C ₂₄ H ₂₆ N ₄ O ₆ 1.4 CF ₃ COOH 1 H ₂ O analysis, calculated: C, 49.97; H, 4.60; N, 8.70. Found: 49.94; H, 4.84; N, 8.56.

  3- (1,3-benzodioxol-5-yl) -4- (3- {2- [6- (methylamino) pyridin-2-yl] ethoxy} isoxazol-5-yl) butanoic acid:

Step 1: Synthesis of 2- [6- (methylamino) pyridin-2-yl] ethanol

  According to the synthesis method described in International Patent WO 2002088118.

Step 2: Ethyl 3- (1,3-benzodioxol-5-yl) -4- (3- {2- [6- (methylamino) pyridin-2-yl] ethoxy} isoxazol-5-yl) Synthesis of butanoate

  2- [6- (Methylamino) pyridin-2-yl] ethanol was used as a starting material and was synthesized by the same synthesis method as in Example 125, Step 10.

Step 3: 3- (1,3-Benzodioxol-5-yl) -4- (3- {2- [6- (methylamino) pyridin-2-yl] ethoxy} isoxazol-5-yl) butane Acid synthesis

Product, ethyl 3- (1,3-benzodioxol-5-yl) -4- (3- {2- [6- (methylamino) pyridin-2-yl] ethoxy} isoxazol-5-yl) Butanoate (453 mg, 0.62 mmol) was dissolved in 3 mL of methanol and 3 mL of 1N sodium hydroxide solution. The reaction was stirred at room temperature overnight, concentrated, acidified with 1 mL trifluoroacetic acid, and as eluent (H ₂ O / TFA) / CH ₃ CN (2.5 mL TFA in 4 L H ₂ O). Was purified by reverse phase HPLC using to give 135 mg of the desired product as a yellow oil. FAB-MS: (MH +) = 426.H NMR (500 MHz, CD ₃ OD) δ 2.55-2.68 (m, 2H), 2.93-3.05 (m, 5H), 3.23 (t, 2H), 3.40 (m, 1H), 4.47 (t, 2H), 5.61 (s, 1H), 5.88 (s, 2H), 6.64-6.74 (m, 3H), 6.89 (d, 1H), 7.81 (t, 1H). C ₂₂ H ₂₃ N ₃ O ₆ 1.2 CF ₃ COOH 1 H ₂ O analysis, calculated: C, 50.50; H, 4.55; N, 7.24. Found: 50.23; H, 4.71; N, 7.27.

  3- (6-Methoxypyridin-3-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] isoxazol-5-yl} Butanoic acid:

Step 1: Synthesis of 7-ethoxy-3- (6-methoxypyridin-3-yl) -5,7-dioxoheptanoic acid

To a solution of anhydrous EtOAc (9.27 mL, 94.9 mmol) in anhydrous THF (37 mL) at −78 ° C. under Ar gas was added lithium diisopropylamide (2M in heptane / THF / ethylbenzene, 47.5 mL, 94 .9 mmol) was added slowly. The resulting solution was stirred at −78 ° C. for 25 minutes and 4- (6-methoxypyridin-3-yl) dihydropyran-2,6 (in anhydrous THF (250 mL) under −78 ° C. Ar gas. A solution of 3H) -dione (synthesized below: 10 g, 45.2 mmol) was added dropwise via cannula. The reaction mixture was stirred at −78 ° C. for 1.5 hours. The mixture was quenched with 2N HCl in ether (100 mL) and allowed to warm to room temperature. Water (200 mL) was added to the reaction mixture and extracted with EtOAc (100 mL, twice). The aqueous layer was basified to pH 4 with 2N NaOH solution and extracted with EtOAc (150 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 80% EtOAc / hexanes to give 2.28 g of the title compound as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.24 (t, 3H), 2.57-2.81 (m, 4H), 2.86-3.03 (m, 2H), 3.66 (m, 1H), 4.15 (m, 2H), 6.69 (d, 1H), 7.46 (dd, 1H), 8.05 (d, 1H).
Synthesis of 4- (6-methoxypyridin-3-yl) dihydropyran-2,6 (3H) -dione

Step 1: Synthesis of dimethyl 3- (6-methoxypyridin-3-yl) pent-2-enedicarboxylate

Dimethylpent-2-enedicarboxylate (2.86 g, 18.09 mmol), palladium (II) acetate (0.12 g, 0.53 mmol), tri-o in DMF (2.13 mL) -A mixture of triphosphine (0.405 g, 1.33 mmol) and triethylamine (2.0 mL) was degassed and heated at 90 <0> C. To this mixture, 5-bromo-2-methoxypyridine (1) was added dropwise and heated at 90 ° C. overnight. The reaction mixture was cooled to room temperature and the solid was filtered. The filtrate was diluted with water and the mixture was extracted with ethyl acetate (100 mL, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 5-25% ethyl acetate / hexane to give dimethyl 3- (6-methoxypyridin-3-yl) pent-2-enedicarboxy as a pale yellow oil. The rate (0.301 g, 21%) was obtained. ¹ H NMR (CD ₃ OD) δ 8.31 (d, 1 H), 7.88-7.84 (m, 1 H), 6.84 (d, 1 H), 6.33 (s, 1 H), 4.86 (s, 2 H) , 3.95 (s, 3 H), 3.75 (s, 3 H), 3.68 (s, 3 H).

Step 2: Synthesis of 3- (6-methoxypyridin-3-yl) pentanedicarboxylate

Dimethyl 3- (6-methoxypyridin-3-yl) pent-2-enedicarboxylate (0.301 g, 1.13 mmol) in MeOH and 4% palladium on carbon in a standard par bottle. Filled. Hydrogenation was carried out at room temperature and 5 psi for 2 hours.
Mass spectrum of C ₁₃ H ₁₇ NO ₅ (ESI +) m / z 268.40 (M + H) ⁺ .

Step 3: Synthesis of 3- (6-methoxypyridin-3-yl) pentanedioic acid

Dimethyl 3- (6-methoxypyridin-3-yl) pentanedicarboxylate (0.276 g, 1.034 mmol) in THF (17.20 mL) was added to water (17.20 mL) and KOH (0 .58 g) was added. The reaction mixture was stirred at room temperature overnight. Then concentrated hydrochloric acid was added until pH = 2.0. During the addition, the temperature was kept below 50 ° C. The mixture was extracted with ethyl acetate (50 ml, 3 times). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated to a white solid, 3- (6-methoxypyridin-3-yl) pentanedioic acid (0.145 g, 59%) Got. ¹ H NMR (CD ₃ OD) δ 8.05 (d, 1 H), 7.69-7.65 (m, 1 H), 6.78 (d, 1 H), 3.89 (s, 3 H), 3.60-3.51 (m, 1 H), 2.80-2.73 (m, 2 H), 2.65-2.58 (m, 2 H); MS (ESI +) m / z 240.30 (M + H) ^{+ of} C ₁₁ H ₁₃ NO ₅ . Step 4: Synthesis of 4- (6-methoxypyridin-3-yl) dihydropyran-2,6 (3H) -dione

  To 3- (6-methoxypyridin-3-yl) pentanedioic acid (0.276 g, 1.15 mmol) was added acetic anhydride (10.0 mL). The reaction mixture was stirred and heated at 100 ° C. for 5 hours. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure to give a dark brown solid, 4- (6-methoxypyridin-3-yl) dihydropyran-2,6 (3H) -dione (0.086 g, 34%). The sample was diluted with acetonitrile, and LCMS was performed by adding 50 uL of piperidine. According to LCMS, the mass of the product was 307.40 m / z (M + piperidine).

Step 2: Synthesis of ethyl 4- (3-hydroxyisoxazol-5-yl) -3- (6-methoxypyridin-3-yl) butanoate

Prepared in the same manner as in Example 125, step 9 using 7-ethoxy-3- (6-methoxypyridin-3-yl) -5,7-dioxoheptanoic acid as the starting material. H NMR (400 MHz, CDCl ₃ ) δ 1.19 (t, 3H), 2.63-2.76 (m, 2H), 2.97-3.09 (m, 2H), 3.55 (m, 1H), 3.98 (s, 3H), 4.07 (m, 2H), 3.51 (s, 1H), 6.33 (d, 1H), 7.62 (dd, 1H), 8.14 (d, 1H).

Step 3: Synthesis of 7- (2-bromoethyl) -1,2,3,4-tetrahydro-1,8-naphthyridine

To a solution of 2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethanol (1 g, 5.62 mmol) in benzene (20 mL) at room temperature under argon. Thionyl bromide (0.65 mL, 8.42 mmol) was added and the reaction mixture was stirred at 75 ° C. overnight. After cooling to room temperature, the solvent was removed in vacuo. The dark oil was purified by chromatography on silica gel (eluent, 40:60 CH ₂ Cl ₂ / ethyl acetate) to give 7- (2-bromoethyl) -1,2,3,4-tetrahydro-1,8. -Naphthyridine was obtained.

Step 4: Ethyl 3- (6-methoxypyridin-3-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] isoxazole- Synthesis of 5-yl} butanoate

7- (2-Bromoethyl) -1,2,3,4-tetrahydro-1,8-naphthyridine (156 mg, 0.65 mmol), DMF (6 mL), ethyl 4- (3-hydroxyisoxazol-5-yl A mixture of) -3- (6-methoxypyridin-3-yl) butanoate (180 mg, 0.59 mmol) and K ₂ CO ₃ (179 mg, 1.3 mmol) was heated at 60 ° C. overnight. The mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine and then dried over sodium sulfate. The solvent was removed and the residue was purified by reverse phase HPLC using (H ₂ O / TFA) / CH ₃ CN (2.5 mL TFA in 4 L H ₂ O) as eluent as a yellow oil. 140 mg of the title compound were obtained. H NMR (400 MHz, CD ₃ OD) δ 0.98 (t, 3H), 1.71 (m, 2H), 2.50-2.70 (m, 4H), 2.78-3.00 (m, 4H), 3.34 (m, 3H), 3.76 (s, 3H), 3.86 (q, 2H), 4.27 (t, 2H), 5.54 (s, 1H), 6.51 (d, 1H), 6.73 (d, 1H), 7.43 (d, 1H), 7.60 (dd, 1H), 7.82 (d, 1H).

Step 5: 3- (6-Methoxypyridin-3-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] isoxazole-5 -Il} butanoic acid synthesis

Product, ethyl 3- (6-methoxypyridin-3-yl) -4- {3- [2- (5,6,7,8, -tetrahydropyrido-1,8-naphthyridin-2-yl) ethoxy Isoxazol-5-yl} butanoate (140 mg, 0.30 mmol) was dissolved in 2 mL methanol and 2 mL 1N sodium hydroxide solution. The reaction was stirred at room temperature overnight, concentrated, acidified with 1 mL of trifluoroacetic acid and reversed using (H ₂ O / TFA) / CH ₃ CN (2.5 mL of TFA in 4 L of water) as eluent. Purification by phase HPLC afforded 85 mg of the desired product as a yellow oil. FAB-MS: (MH +) = 439. H NMR (500 MHz, CD ₃ OD) δ 1.92 (m, 2H), 2.62-2.79 (m, 2H), 2.82 (t, 2H), 3.00 (m, 1H), 3.08-3.14 (m, 3H), 3.49 (m, 3H), 3.90 (s, 1H), 4.42 (t, 2H), 5.68 (s, 1H), 6.65 (d, 1H), 6.83 (d, 1H), 7.57 (d, 1H), 7.71 (dd, 1H), 7.95 (d, 1H) .C ₂₃ H ₂₆ N ₄ O ₅ plus 2.8 CF ₃ COOH and 1 H ₂ O analysis, calculated: C, 44.28; H, 4.00; N, 7.22. Found: 44.25; H, 4.39; N, 7.20.

  3- (2,3-Dihydro-benzofuran-6-yl) -4- {5- [3- (5,6,7,8-tetrahydro- [1,8] naphthyridin-2-yl) propyl] -4H -[1,2,4] triazol-3-yl} -butyric acid:

The activity of the compounds of the present invention was tested in the following assay. The compounds of the present invention, Arufabuibeta ₃ integrin and indicates antagonism, the 293 cell assay _{IC 50} of a 0.1NM～100myuM. Likewise, these compounds showed Arufabuibeta ₅ both antagonism, cell adhesion method _{IC 50} of less than 50 [mu] M.

Vitronectin adhesion assay
Vitronectin receptor Arufabuibeta ₃ and Arufabuibeta ₅ materials human conventional literature "Pytela et al, Methods in Enzymology, 144: 475-489 (1987) " as documented in, purified from human placenta. Human vitronectin was purified from fresh frozen plasma as described in the previous literature “Yatohgo et al., Cell Structure and Function , 13: 281-292 (1988)”. Biotinylated human vitronectin was obtained from NHS obtained from Pierce Chemical Company (Rockford, IL) as described in the previous literature "Charo et al., J. Biol. Chem. , 266 (3): 1415-1421 (1991)". -Prepared by coupling biotin to purified biotin. Assay buffer, OPD substrate tablets and RIA grade BSA were obtained from Sigma (St. Louis, MO). Anti-biotin antibody was obtained from Sigma (St. Louis, MO). Nalge Nunc-Immuno microtiter plates were obtained from the Nalge Company (Rochester, NY).

Method
Solid Phase Receptor Assay This assay was essentially the same as reported in the previous literature “Niiya et al., Blood , 70: 475-483 (1987)”. Concentration of purified human vitronectin receptor Arufabuibeta ₃ and Arufabuibeta ₅ from a stock solution, Ca ⁺⁺ of 1.0 mM, Mg ⁺⁺ and Mn ⁺⁺ containing Tris buffered saline (TBS ^+++, pH 7.0) in Was diluted to 1.0 μg / mL. Diluted receptors were immediately transferred to Nalge Nunc-Immuno microtiter plates at 100 μL / well (100 ng receptor / well). These plates were sealed and incubated overnight at 4 ° C. to allow the receptor to bind to the wells. All remaining steps were performed at room temperature. After these assay plates were emptied, by adding 1% RIA Grade BSA (TBS ⁺⁺⁺ / BSA) 200μL of in TBS ^+++, it blocked the plastic surface from the outside air. After incubation for 2 hours, the assay plate was washed with TBS ⁺⁺⁺ using a 96-well plate washer. Logarithmic serial dilutions of test compounds and control samples began with a stock concentration of 2 mM and 2 nM biotinylated vitronectin in TBS ⁺⁺⁺ / BSA was used as the diluent. Such premixing of labeled and test (or control) ligands and subsequent transfer to 50 μL aliquots of assay plates is performed on a CETUS Propette robot to a final concentration of labeled ligand of 1 nM and the test compound. The highest concentration was 1.0 × 10 ⁻⁴ M. A competitive reaction occurred for 2 hours, after which all holes were washed with a plate washer as described above. Affinity-purified horseradish peroxidase-labeled anti-biotin antibody (goat) was diluted 1: 2000 in TBS ⁺⁺⁺ / BSA and 125 μL was placed in each well. After 45 minutes, the plates were washed and incubated with OPD / H ₂ O ₂ substrate (pH 5.0) in 100 mM / L citrate buffer. The plate was read at a wavelength of 450 nm using a microtiter plate reader and when the maximum binding control hole reached an absorbance of about 1.0, the final A ₄₅₀ was recorded as the analytical value. Data was analyzed using macro written for EXCEL spreadsheet program. Mean, standard deviation and% CV were determined by concentration measurement in two series. Mean _A450 values were normalized to the average of the four maximum binding control values (no competitor added) (B-MAX). The normalized values are plotted on a semi-logarithmic scale through a four-variable curve fitting algorithm (see “Rodbard et al., Int. Atomic Energy Agency, Vienna, pp 469 (1977)”) to determine the maximum binding of biotinylated vitronectin. The concentration corresponding to 50% inhibitory concentration (IC ₅₀ ) and the concentration corresponding to R ² were determined for compounds that exceeded 50% inhibition at the maximum test concentration. When not determined, the IC ₅₀ is reported as a value above the maximum test concentration. Β-[[2-[[5-[(Aminoiminomethyl) amino] -1-oxopentyl] amino] -1-oxoethyl] amino, a potent αvβ ₃ antagonist (IC _{50 in} the range of 3-10 nM) ] -3-Pyridinepropanoic acid (Example 1 of US Pat. No. 5,602,155) was included in each plate as a positive control.

Purified IIb / IIIa receptor assay
Materials Human fibrinogen receptor (IIb / IIIa) was purified from outdated platelets (Pytela, R., Pierschbacher, MD, Argraves, S., Suzuki, S., and Rouslahti, E. "Arginine- Glycine-Aspartic acid adhesion receptors ", Method in Enzymology 144 (1987): 475-489"). Human vitronectin has been described in the literature "Yatohgo, T., Izumi, M., Kashiwagi, H., and Hayashi, M.," Novel purification of in vitro nectin from human plasma by heparin affinity chromatography, " Cell Structure and Function 13 (1988): 281-292 "was purified from fresh frozen plasma. Biotinylated human vitronectin was prepared as previously described by coupling NHS-biotin obtained from Pierce Chemical Company (Rockford, IL) to purified vitronectin. (References "Charo, IF, Nannizzi, L., Phillips, DR, Hsu, MA, Scarborough, RM," Inhibition of fibrinogen binding to GP IIb / IIIa by a GP IIa peptide ", J. Biol. Chem. 266 (3 (1991): 1415-1421].) Assay buffer, OPD substrate tablets, and RIA grade BSA were obtained from Sigma (St. Louis, MO). Anti-biotin antibody was obtained from Sigma (St. Louis, MO). Nalge Nunc-Immuno microtiter plates were obtained from the Nalge Company (Rochester, NY). ADP reagent was obtained from Sigma (St. Louis, MO).

Method
Solid Phase Receptor Assay This assay is based on the conventional literature "Niiya, K., Hodson, E., Bader, R., Byers-Ward, V. Koziol, JA, Plow, EF, and Ruggeri, ZM," Increased surface expression of the membrane glycoprotein IIb / IIIa complex induced by platelet activation: Relationships to the binding of fibrinogen and platelet aggregation ", Blood , 70: 475-483 (1987): 475-483" Is the same. Purified human fibrinogen receptor (IIb / IIIa) is diluted from stock solution in Tris buffered saline (TBS ⁺⁺⁺ , pH 7.0) containing 1.0 mM Ca ⁺⁺ , Mg ⁺⁺ and Mn ^++. The receptor concentration was 1.0 μg / mL. The diluted receptor was immediately transferred to Nalge Nunc-Immuno microtiter plates at 100 μL / well (100 ng receptor / well). The plates were sealed and incubated overnight at 4 ° C. to facilitate binding to the receptor wells. All remaining steps were performed at room temperature. These assay plates were emptied, by adding 1% RIA Grade BSA (TBS ⁺⁺⁺ / BSA) 200μL of in TBS ^+++, it blocked the plastic surface from the outside air. After incubation for 2 hours, the assay plate was washed with TBS ⁺⁺⁺ using a 96-well plate washer. Logarithmic serial dilutions of test compounds and control samples were started at a stock concentration of 2 mM using 2 nM biotinylated vitronectin in TBS ⁺⁺⁺ / BSA as diluent. Such premixing of labeled and test (or control) ligands and subsequent transfer to 50 μL aliquots of assay plates is carried out using a CETUS Propette robot with a final concentration of labeled ligand of 1 nM and test compounds. Was set to 1.0 × 10 ⁻⁴ M. A competitive reaction occurred for 2 hours, and then all holes were washed with a plate washer as before. Affinity-purified horseradish peroxidase labeled anti-biotin antibody (goat) was diluted 1: 2000 in TBS ⁺⁺⁺ / BSA and 125 μL was placed in each well. After 45 minutes, the plates were washed and incubated with ODD / H ₂ O ₂ substrate in 100 mM / L citrate buffer (pH 5.0). The plate was read with a microtiter plate reader at a wavelength of 450 nm, and when the maximum binding control hole reached an absorbance of about 1.0, the final A ₄₅₀ was recorded as the analytical value. Data was analyzed using macro written for EXCEL spreadsheet program. Mean, standard deviation and% CV were determined by concentration measurement in two series. Average _A450 values were normalized to the average of the four maximum binding control values (no competitor added) (B-MAX). The normalized value is applied to a four-variable curve fitting algorithm (see literature “Rodbard et al., Int. Atomic Energy Agency, Vienna, pp 469 (1977))” and plotted on a semi-log scale to determine the maximum binding of biotinylated vitronectin. The concentration corresponding to 50% inhibition (IC ₅₀ ) was calculated and the corresponding R ² was determined for compounds that exceeded 50% inhibition at the maximum test concentration. When not determined, the IC ₅₀ is reported as a value above the maximum test concentration. Β-[[2-[[5-[(Aminoiminomethyl) amino] -1-oxopentyl] amino] -1-oxoethyl] amino, a potent αvβ ₃ antagonist (IC _{50 in} the range of 3-10 nM) ] -3-Pyridinpropanoic acid (US Pat. No. 5,602,155, Example 1) was included on each plate as a positive control.

Human Platelet-rich Plasma Assay Healthy donors who have not taken aspirin were selected from a volunteer population. Platelet-rich plasma collection and subsequent ADP-induced platelet aggregation assay was performed according to the method described by Zucker, MB, “Platelet Aggregation Measured by the Photometric Method”, Methods in Enzymology 169 (1989): 117-133. did. 45 mL of whole blood was collected in a 60 mL syringe containing 5 mL of 3.8% trisodium citrate by a standard venous blood collection method using a butterfly needle. After the syringe was shaken well, the whole blood containing the anticoagulant was transferred to a 50 mL polyethylene conical tube, and this blood was centrifuged at 200 × g for 12 minutes at room temperature to precipitate cells without platelets. Platelet rich plasma was transferred to a polyethylene tube and stored at room temperature until use. The remaining blood was subjected to a second centrifugation at 2000 × g for 15 minutes to obtain platelet-poor plasma. The platelet count is typically 300,000 to 500,000 per microliter. Platelet rich plasma (0.45 mL) was aliquoted into silicone-treated cuvettes and stirred (1100 rpm) at 37 ° C. for 1 minute before adding 50 uL of test compound before dilution. One minute after mixing, aggregation began with the addition of 50 uL of 200 uM ADP. Aggregation was recorded for 3 minutes using a Peyton 2-channel aggregometer (Payton Scientific, Buffalo, NY). Dose-response curves were generated using% inhibition of maximal response (control is saline) for a series of dilutions of test compound. All compounds were tested in duplicate and the half-concentration showing the maximum inhibition (IC ₅₀ ) was determined from the dose-response curve for compounds showing more than 50% inhibition at the maximum test concentration. When not determined, the IC ₅₀ is reported as exceeding the maximum test concentration.

The beta ₃ subunit cell assays Arufabuibeta ₃ regarding potency and selectivity while known only to form a complex with .alpha.v or alpha _IIb, .alpha.v subunit to form a complex with a plurality of beta subunit. Three αv integrins most homologous with the Arufabuibeta ₃ is Arufabuibeta _1, a Arufabuibeta ₅ and Arufabuibeta _6, amino acids match rate in β subunits, 43% respectively, 56% and 47%. To evaluate the selectivity of the compound with the integrin Arufabuibeta ₃ and integrin αvβ _6, 293 human embryonic kidney cell line cell-based assay using the already established. The 293 cell line, Arufabuibeta ₁ express the, not little or no detect Arufabuibeta ₃ or αvβ _6. The cDNAs corresponding to β ₃ and β ₆ were separately transferred into the 293 cell line, producing 293-β ₃ cells and 293-β ₆ cells, respectively. High expression of Arufabuibeta ₃ and Arufabuibeta ₆ at the cell surface was confirmed by flow cytometry. Conditions have already been established for each cell line where appropriate integrins are involved in cell adhesion to human immobilized vitronectin, as measured by a panel of integrin-specific monoclonal neutralizing antibodies. Briefly, adherent cells are detected by incubating cells with inhibitors in the presence of 200 uM Mn2 ⁺ , adhering and washing with immobilized vitronectin, and measuring endocrine alkaline phosphatase and para-nitrophenyl phosphate. . Eight-point dose-response curves using 10-fold or 3-fold dilutions of compounds were evaluated by applying a 4-variable logistic nonlinear model (using SAS). To evaluate the efficacy of compounds against membrane bound αvβ _6, another cell-based adhesion assay has been established using the HT-29 human colon carcinoma cell line. High expression of Arufabuibeta ₆ in HT-29 cell surface was confirmed by flow cytometry. As measured by integrin-specific neutralizing monoclonal antibodies panels, αvβ ₆ in cell adhesion to human immobilization cryptic associated peptide (LAP) is a condition when being involved is already established. Briefly, adherent cells were incubated with inhibitors in the presence of 200 uM Mn ²⁺ , adhered to and washed with immobilized LAP, and adherent cells were quantified using para-nitrophenyl phosphate to quantify endocrine alkaline phosphatase. To detect. Eight-point dose-response curves using 10-fold or 3-fold dilutions of the compounds were evaluated by applying a 4-variable logistic nonlinear model (using SAS). Evaluation compounds were relatively ineffective in that they inhibit cell adhesion Arufabuibeta ₆ involved. Arufabuibeta ₆ also, since can affect normal physiological process of tissue repair is normally occurs in skin and lung tissue and cellular metabolism, selective antagonism of Arufabuibeta ₃ integrin, to compounds of this type It is considered desirable.

Claims (5)

A pharmaceutically acceptable carrier as well as:
3- (3,5-ditert-butylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid (TFA salt);
3- (3-tert-butyl-5-iodophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid;
3- (3-tert-butyl-5-bromophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid;
3- (5-tert-butyl-2-hydroxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid;
3- [3,5-ditert-butyl-2- (carboxymethoxy) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (5-tert-butyl-2-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid;
3- (3,5-ditert-butyl-4-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl]- 1,2,4-oxadiazol-5-yl} butanoic acid;
3- {3-tert-butyl-5- [2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl] -phenyl} -4- {3- [3- (5,6 , 7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3,4-Dichlorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 trifluoroacetic acid -Oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- (3-fluoro-4-methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid;
3- (4-Phenoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid;
3- (1-Benzofuran-2-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetate , 4-oxadiazol-5-yl} butanoic acid;
3- [4- (Benzyloxy) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetic acid , 4-oxadiazol-5-yl} butanoic acid;
3- [4- (Methylsulfonyl) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetic acid , 4-oxadiazol-5-yl} butanoic acid;
Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3- [4- (trifluoromethoxy) phenyl] butanoic acid;
3- (3-Furyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxatriacetate Diazol-5-yl} butanoic acid;
Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3-thien-3-yl-butanoic acid;
Hydrochloric acid 3- (2,3-dihydro-1,4-benzodioxin-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl ) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} -3- [3- (trifluoromethoxy) phenyl] butanoic acid;
Hydrochloric acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} -3- (3,4,5-trifluorophenyl) butanoic acid;
Hydrochloric acid 3- (2,2-difluoro-1,3-benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- [3-fluoro-5- (trifluoromethyl) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl]- 1,2,4-oxadiazol-5-yl} butanoic acid;
3- (6-methoxy-2-naphthyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 hydrochloride -Oxadiazol-5-yl} butanoic acid;
3- (6-Methoxypyridin-3-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 -Oxadiazol-5-yl} butanoic acid;
3- (4-Cyanophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid;
3- (3-Cyanophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} butanoic acid;
3-Benzyl-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole-5 trifluoroacetate -Yl} butanoic acid;
3- (4-Fluoro-3-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, trifluoroacetic acid, 2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- (3-fluoro-5-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid;
3- (2-Methyl-1,3-benzothiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl hydrochloride ] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- [2- (4-chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3-[(2- (4-methoxyphenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine- 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (2-Methyl-1,3-benzothiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl hydrochloride ] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- [2- (3,5-Difluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine hydrochloride -2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- [2- (3,4-Difluorophenyl) -1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine hydrochloride -2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- [2- (2-furyl) 1,3-thiazol-5-yl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl ) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3,4-Dimethoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid;
3- (3,5-dimethoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid;
3- (3,5-dichlorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 trifluoroacetic acid -Oxadiazol-5-yl} butanoic acid;
3- (3,5-Difluorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid;
3- (3-Fluoro-4-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 trifluoroacetic acid , 4-oxadiazol-5-yl} butanoic acid;
Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3- [4- (trifluoromethyl) phenyl] butanoic acid;
3- (2-Methyl-1,3-thiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) trifluoroacetate Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1-Phenyl-1H-pyrazol-4-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] trifluoroacetate -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1-Benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4 hydrochloride -Oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3- (2,3-dihydro-1-benzofuran-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (3- {3-[(pyridin-2-ylamino) methyl] phenyl} -1,2,4-oxadiazole-5 hydrochloride -Yl) butanoic acid;
3- (7-Fluoro-1,3-benzodioxol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-2) trifluoroacetic acid -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1,3-Benzoxazol-6-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1 hydrochloride , 2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Methyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-trifluoroacetic acid 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Ethyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-trifluoroacetic acid 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Phenyl-1,2,4-oxadiazol-5-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridine-trifluoroacetic acid 2-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
Trifluoroacetic acid [1-benzoyl-4-({3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole -5-yl} methyl) piperidin-4-yl] acetic acid;
Trifluoroacetic acid [1-benzoyl-4-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) piperidin-4-yl] acetic acid ;
Trifluoroacetic acid [1- (tert-butoxycarbonyl) -4-({3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} methyl) piperidin-4-yl] acetic acid;
Trifluoroacetic acid [1- (tert-butoxycarbonyl) -4-({3- [4- (pyridin-2-ylamino) butyl] -1,2,4-oxadiazol-5-yl} methyl) piperidine- 4-yl] acetic acid;
3- (4-Methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid;
3- (3-Chlorophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole hydrochloride -5-yl} butanoic acid;
Hydrochloric acid 3- (4-methoxy-3-methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, 4-oxadiazol-5-yl} butanoic acid;
3- [4- (Methylthio) phenyl] -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2, trifluoroacetic acid 4-oxadiazol-5-yl} butanoic acid;
3- (1-Methyl-1H-indol-3-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] trifluoroacetate -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1,1′-biphenyl-4-yl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, 2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Bromophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid;
3- (4-Bromophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid;
3- (3-phenoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-trifluoroacetic acid Oxadiazol-5-yl} butanoic acid;
Hydrochloric acid 3-[(3- (benzyloxy) phenyl)]-4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2 , 4-oxadiazol-5-yl} butanoic acid;
3- (3-Bromo-4-methoxyphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, trifluoroacetic acid, 2,4-oxadiazol-5-yl} butanoic acid;
Trifluoroacetic acid 4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazol-5-yl}- 3- (3,4,5-trimethoxyphenyl) butanoic acid;
3- (2-Naphtyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole hydrochloride -5-yl} butanoic acid;
3- (3-Nitrophenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid;
3- (3-Methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid;
3- (2-Furyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadiazole hydrochloride -5-yl} butanoic acid;
3- (2-Methylphenyl) -4- {3- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,2,4-oxadi hydrochloride Azol-5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6 -Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
4- {3- [3- (3,4-Dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) propyl] -1,2,4-oxadiazole-5 -Yl} -3- (3,5, -dimethoxyphenyl) butanoic acid, TFA;
3-Benzo [1,3] dioxol-5-yl-4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene-2- Yl) -propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3- (3-Fluoro-4-methoxyphenyl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl ) -Propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3- (3,5-difluorophenyl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl)- Propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3- (3,5-Dimethoxyphenyl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-2-yl)- Propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3- (2-Methylbenzothiazol-5-yl) -4- {3- [3- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene-2- Yl) -propyl]-[1,2,4] oxadiazol-5-yl} -butyric acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (1,2,3,5-tetrahydropyrido [2,3-e] [1,4] oxazepine -8-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid, TFA;
3- (3,5-Dimethoxyphenyl) -4- {3- [3- (1,2,3,5-tetrahydropyrido [2,3-e] [1,4] oxazepin-8-yl) propyl ] -1,2,4-oxadiazol-5-yl} butanoic acid, TFA;
Hydrochloric acid 3- (1,3-benzodioxol-5-yl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] -propyl} -1,2,4-oxa Diazol-5-yl) butanoic acid;
3- (3-Fluorophenyl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] propyl} -1,2,4-oxadiazol-5-yl) trifluoroacetate Butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (3- {3- [6- (ethylamino) pyridin-2-yl] propyl} -1,2,4-trifluoroacetic acid Oxadiazol-5-yl) butanoic acid;
3- (3-Fluorophenyl) -4- (3- {3- [6- (methylamino) pyridin-2-yl] propyl-1,2,4-oxadiazol-5-yl) butane trifluoroacetate acid;
3- (1,3-Benzodioxol-5-yl) -4- (3- {4-[(4-methylpyridin-2-yl) amino] butyl} -1,2,4-oxadiazole -5-yl) butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (3- {4-[(6-methylpyridin-2-yl) amino] butyl} -1,2,4-oxadiazole -5-yl) butanoic acid;
(2- {6- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] pyridin-3-yl} cyclopropyl) acetic acid;
3-methyl-4- {6- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] pyridin-3-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl trifluoroacetate ] -1,3,4-oxadiazol-2-yl} butanoic acid;
3- (3-Fluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3,4-trifluoroacetic acid Oxadiazol-2-yl} butanoic acid;
3- (3-Fluoro-4-methoxyphenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1, trifluoroacetic acid, 3,4-oxadiazol-2-yl} butanoic acid;
3- (3,5-Dimethoxyphenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3, trifluoroacetic acid 4-oxadiazol-2-yl} butanoic acid;
3- (2-Methyl-1,3-thiazol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) trifluoroacetic acid Propyl] -1,3,4-oxadiazol-2-yl} butanoic acid;
3- (4-Fluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3,4-trifluoroacetic acid Oxadiazol-2-yl} butanoic acid;
3- (3,5-Difluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3, trifluoroacetic acid 4-oxadiazol-2-yl} butanoic acid;
3- (3,5-Difluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3, trifluoroacetic acid 4-thiadiazol-2-yl} butanoic acid;
3- (4-Fluorophenyl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1,3,4-trifluoroacetic acid Thiadiazol-2-yl} butanoic acid;
3- (2-Methyl-1,3-thiazol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) trifluoroacetic acid Propyl] -1,3,4-thiadiazol-2-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl trifluoroacetate ] -1,3,4-thiadiazol-2-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] isoxazole- 5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -2H -Tetraazol-2-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {5- [3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) propyl] -1H -Tetraazol-1-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] -1H -Pyrazol-5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] isoxazol-5-yl} butanoic acid ;
3- [2- (4-Chlorophenyl) -1,3-thiazol-5-yl] -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ) Ethoxy] isoxazol-5-yl} butanoic acid;
3 -Benzo [1,3] dioxol-5-yl-4- {3- [2- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene-2- Yl) -ethoxy] -isoxazol-5-yl} -butyric acid;
3-Benzo [1,3] dioxol-5-yl-4- {3-oxo-2- [2- (6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohept Ten-2-yl) -ethyl] -2,3-dihydro-isoxazol-5-yl} -butyric acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6 -Yl) ethoxy] isoxazol-5-yl} butanoic acid, TFA;
3- (1,3-Benzodioxol-5-yl) -4- {2- [2- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6 -Yl) ethyl] -3-oxo-2,3-dihydroisoxazol-5-yl} butanoic acid, TFA;
3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (1,2,3,5-tetrahydropyrido [2,3-e] [1,4] oxazepine -8-yl) ethoxy] isoxazol-5-yl} butanoic acid, TFA;
3- (1,3-Benzodioxol-5-yl) -4- {3-oxo-2- [2- [1,2,3,5-tetrahydropyrido [2,3-e] [1 , 4] Oxazepine-8-yl] ethyl] -2,3-dihydroisoxazol-5-yl} butanoic acid, TFA;
3- (1,3-Benzodioxol-5-yl) -4- (3- {2- [5- (methoxymethyl) -6- (methylamino) pyridin-2-yl] ethoxy} isoxazole-5 -Yl) butanoic acid, TFA;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (5,5-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine- 6-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (2-Methyl-1,3-benzothiazol-5-yl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] Pyrazin-6-yl) propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (3-Fluoro-4-methoxyphenyl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (6-Methoxypyridin-3-yl) -4- {3- [3- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl) Propyl] -1,2,4-oxadiazol-5-yl} butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (3-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl] thio } -1H-1,2,4-triazol-5-yl) butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (1-methyl-5-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ) Ethyl] thio} -1H-1,2,4-triazol-3-yl) butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- (4-methyl-5-{[2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ) Ethyl] thio} -4H-1,2,4-triazol-3-yl) butanoic acid;
3- (1,3-Benzodioxol-5-yl) -4- {3- [2- (1-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine- 6-yl) ethoxy] isoxazol-5-yl} butanoic acid;
3- (1,3-benzodioxol-5-yl) -4- (3- {2- [6- (methylamino) pyridin-2-yl] ethoxy} isoxazol-5-yl) butanoic acid; and 3- (6-Methoxypyridin-3-yl) -4- {3- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy] isoxazol-5-yl} A pharmaceutical composition comprising a compound selected from the group consisting of butanoic acid. therapeutic treatment or prophylaxis of conditions Arufabuibeta ₃ integrin is involved, in a mammal in need of such treatment, a method for the treatment or prevention of a composition according to claim 1 to a subject Said method comprising administering a pharmaceutically effective amount.   The conditions to be treated are tumor metastasis, solid tumor growth, angiogenesis, osteoporosis, malignant humoral calciumemia, smooth muscle cell migration, restenosis, atherosclerosis, macular degeneration, retina 3. The method of claim 2, wherein the method is selected from the group consisting of symptom and arthritis. therapeutic treatment or prophylaxis of conditions Arufabuibeta ₅ integrins are involved, in a mammal in need of such treatment, a method for the treatment or prevention of a composition according to claim 1 to a subject Said method comprising administering a pharmaceutically effective amount.   The conditions to be treated are tumor metastasis, solid tumor growth, angiogenesis, osteoporosis, malignant humoral calciumemia, smooth muscle cell migration, restenosis, atherosclerosis, macular degeneration, retina 5. The method of claim 4, wherein the method is selected from the group consisting of disease and arthritis.